breast cancer thesis 2021

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Breast cancer—epidemiology, risk factors, classification, prognostic markers, and current treatment strategies—an updated review.

Simple Summary

1. introduction, 2. breast cancer epidemiology, 3. risk factors of breast cancer, 3.1. non-modifiable factors, 3.1.1. female sex, 3.1.2. older age, 3.1.3. family history, 3.1.4. genetic mutations, 3.1.5. race/ethnicity, 3.1.6. reproductive history, 3.1.7. density of breast tissue, 3.1.8. history of breast cancer and benign breast diseases, 3.1.9. previous radiation therapy, 3.2. modifiable factors, 3.2.1. chosen drugs, 3.2.2. physical activity, 3.2.3. body mass index, 3.2.4. alcohol intake, 3.2.5. smoking, 3.2.6. insufficient vitamin supplementation, 3.2.7. exposure to artificial light, 3.2.8. intake of processed food/diet, 3.2.9. exposure to chemical, 3.2.10. other drugs, 4. breast cancer classification, 4.1. histological classification, 4.2. luminal breast cancer, 4.3. her2-enriched breast cancer, 4.4. basal-like/triple-negative breast cancer, 4.5. claudin-low breast cancer, 4.6. surrogate markers classification, 4.7. american joint committee on cancer classification, 5. prognostic biomarkers, 5.1. estrogen receptor, 5.2. progesterone receptor, 5.3. human epidermal growth factor receptor 2, 5.4. antigen ki-67, 5.6. e-cadherin, 5.7. circulating circular rna, 5.9. microrna, 5.10. tumor-associated macrophages, 5.11. inflammation-based models, 5.11.1. the neutrophil-to-lymphocyte ratio (nlr), 5.11.2. lymphocyte-to-monocyte ratio, 5.11.3. platelet-to-lymphocyte ratio (plr), 6. treatment strategies, 6.1. surgery, 6.2. chemotherapy, 6.3. radiation therapy, 6.4. endocrinal (hormonal) therapy, 6.5. biological therapy, 7. conclusions, author contributions, conflicts of interest.

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Share and Cite

Łukasiewicz, S.; Czeczelewski, M.; Forma, A.; Baj, J.; Sitarz, R.; Stanisławek, A. Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review. Cancers 2021 , 13 , 4287. https://doi.org/10.3390/cancers13174287

Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review. Cancers . 2021; 13(17):4287. https://doi.org/10.3390/cancers13174287

Łukasiewicz, Sergiusz, Marcin Czeczelewski, Alicja Forma, Jacek Baj, Robert Sitarz, and Andrzej Stanisławek. 2021. "Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review" Cancers 13, no. 17: 4287. https://doi.org/10.3390/cancers13174287

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REVIEW article

Evolving trends in surgical management of breast cancer: an analysis of 30 years of practice changing papers.

• 1 The Department of Surgery, The Royal College of Surgeons in Ireland, Dublin, Ireland
• 2 The Department of Surgery, Beaumont Hospital, Dublin, Ireland

The management of breast cancer has evolved into a multidisciplinary evidence-based surgical speciality, with emphasis on conservative surgery. A number of landmark trials have established lumpectomy followed by radiation as the standard of care for many patients. The aim of this study is to construct a narrative review of recent developments in the surgical management of breast cancer and how such developments have impacted surgical practice. A comprehensive literature search of Pubmed was conducted. The latest search was performed on October 31 st , 2020. Search terms “breast cancer” were used in combinations with specific key words and Boolean operators relating to surgical management. The reference lists of retrieved articles were comprehensively screened for additional eligible publications. Articles were selected and reviewed based on relevance. We selected publications in the past 10 years but did not exclude commonly referenced and highly regarded previous publications. Review articles and book chapters were also cited to provide reference on details not discussed in the academic literature. This article reviews the current evidence in surgical management of early-stage breast cancer, discusses recent trends in surgical practice for therapeutic and prophylactic procedures and provides commentary on implications and factors associated with these trends.

Introduction

Breast surgery is a complex multi-disciplinary surgical specialty. The breast surgeon must diagnose and treat breast cancer in symptomatic patients and coordinate the timing of surgery as dictated by systemic and radiation therapies. Treatment varies on a case-by-case basis from breast conserving surgery to mastectomy to specialized oncoplastic techniques and reconstructive procedures. Since the first Halsted radical mastectomy the range of surgical approaches has increased greatly. Following the introduction of the modified radical mastectomy it took almost 30 years for breast conserving surgery and adjuvant radiotherapy became an accepted standard of care ( 1 ).

Breast surgeons further challenged breast conserving surgery (BCS) in pursuit of improving cosmesis while maintaining oncological outcomes. This paradigm shift towards better cosmetic outcomes and quality of life led to the advent of oncoplastic surgery ( 2 ).

This paper will discuss the advances in the surgical management of breast cancer over the last 30 years while also providing an overview of emerging surgical options and the future they bring to the sphere of breast cancer management.

From Mastectomy to Breast Conservation

Breast surgery has undergone significant changes over time. First, Halsted’s radical mastectomy gained widespread acceptance as the standard of care up until 1960's. While this procedure improved local control, the extensive dissection of skin, breast, pectoralis muscles and axillary contents caused significant morbidity ( 3 ). Furthermore, to improve its curative potential some surgeons also excised the internal mammary nodes. This became known as an extended radical mastectomy. However this did not improve patient survival ( 4 , 5 ).

To reduce morbidity, Patey introduced the modified radical mastectomy (MRM) excising the breast, pectoralis major fascia, and level I and II axillary lymph nodes ( 6 ). At the same time McWhirter introduced the simple mastectomy which combined surgery with radiotherapy. Several randomised controlled trials investigated survival outcomes of these two methods compared to Halsted’s radical mastectomy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial observed no significant improvement in survival for patients treated with Halsted radical mastectomy compared to less extensive surgery. NSABP B-04 also found the addition of local-regional radiation to total mastectomy had no significant advantage in overall survival (OS). Additionally, it found that in node negative disease, routine axillary lymph node dissection (ALND) is overly aggressive ( 7 ). As such, this trial heralded the move toward increasingly conservative surgical management of breast cancer along with introducing the first concept of multi-modality therapy.

The NSABP B-06 trial was the first trial to establish BCS as a feasible treatment option for early invasive breast cancer when used in conjunction with radiation ( 8 ). No significant difference in OS or disease-free survival (DFS) was found in patients receiving BCS with or without radiation compared to those receiving modified radical mastectomy. The rate of local regional recurrence (LRR) was significantly higher in those who underwent lumpectomy without radiation ( 8 ).

The Milan Cancer Institute (Milan I Study) further established BCS as the standard of care for early breast cancer (≤2cm in diameter). Despite higher local recurrence in the BCS group, there was no significant difference in long-term survival in those who underwent radical mastectomy compared to BCS and radiotherapy ( 1 ). Table 1 outlines the landmark randomised controlled trials (RCT) in the surgical management of non-invasive and invasive breast cancer. Figure 1 is a timeline of landmark trials in the surgical management of breast cancer.

Figure 1 A timeline of evolving trends in surgical management of breast cancer. OS, overall survival; DFS, disease free survival; BCS, beast conserving surgery; RT, radiotherapy; QOL, quality of life; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection.

Table 1 Landmark RCT’s in the surgical management of the axilla.

BCS focuses on three primary aims; obtain tumour free margins, achieve a good cosmetic outcome, and at least equivalent survival to traditional mastectomy. As such the following contraindications must be considered before proceeding with BCS:

-Multicentric disease - Two or more primary tumours in different quadrants of the breast such that they cannot be removed with a single excision

- Presence of diffuse malignant-appearing calcifications on imaging (mammogram or magnetic resonance imaging [MRI])

-Previous history of chest radiotherapy - which, when combined with the proposed treatment, would result in an excessively high total radiation dose to the chest wall

-Persistently positive margins despite attempts at re-excision

Furthermore, a consideration, but not an absolute contraindication to BCS is a large tumour in a relatively small breast. Neoadjuvant chemotherapy (NACT) is increasingly used in these patients for the purpose of downstaging the tumour and thus, making the patient eligible for BCS ( 12 – 14 ). Notably when compared to adjuvant chemotherapy, those receiving NACT do not benefit in terms of survival and local recurrence ( 12 , 13 , 15 ).

Local recurrence is a risk factor for distant metastasis ( 16 ). The local recurrence rate after BCS (2% at 10 years) is no longer considered higher than that after mastectomy ( 17 , 18 ). Risk factors for local recurrence include young age, positive surgical margins, node positivity, estrogen receptor negativity, and absence of radiation therapy ( 19 ). Surgical margins are a controllable risk factor. Current recommendations for the adequacy of margins are based off a large meta analyses in 2014, which included 1506 ipsilateral breast tumour recurrences (IBTRs) ( 20 ). At a median follow-up of 79 months, the median prevalence of IBTR was 5.3%. A positive margin, defined as “ink on tumour”, was associated with more than a two-fold increase in IBTR. Routine re-excision is not necessary for close positive margins (e.g. <1 mm), however clinical and pathological features should guide decisions to perform a second operation ( 21 , 22 ). Positive margins are associated with a two-fold increase in LRR ( 20 ) and necessitate reoperation. Rates of reoperation vary from less than 10% to more than 50% ( 23 – 25 ).

IncreasING Mastectomy Rates

It was expected that rates of mastectomy would decrease with the availability of screening mammography. However, the effect of screening on surgical treatment has yielded conflicting results ( 26 , 27 ). Increasing rates of prophylactic mastectomies may partially account for unchanged mastectomy rates, offsetting the benefits of advances in BCS ( 28 ). Improvements in reconstruction options have brought about an unanticipated increase in contralateral prophylactic mastectomy rates. A once disfiguring procedure, patients and surgeons are now more aware of symmetry and cosmesis post-surgery. Low satisfaction scores among patients undergoing unilateral mastectomy with implant-based reconstruction suggests cosmetic factors may be a driver of increasing contralateral prophylactic mastectomy rates ( 29 , 30 ).

Furthermore, some patients with early-stage breast cancer who are suitable for BCS, choose to undergo mastectomy instead. While the reasons for this are unclear, they may in part be attributed to a fear of recurrence, thus triggering a move towards more “aggressive” management approaches. However, it is important to note in young patients with early-stage breast cancer, BCS with adjuvant radiotherapy has comparable OS to mastectomy alone ( 31 ). This has been seen in a number of studies which have demonstrated improved OS and DFS in BCS compared to mastectomy ( 32 – 38 ). BCS may in fact have superior LRR compared to mastectomy due to a number of factors ( 39 ), including developments in radiation treatment planning which have resulted in increased coverage of residual breast tissue compared to techniques in original trials. Improvements in imaging modalities have resulted in more accurate selection of patients for BCS i.e. those without multicentric disease. Finally, with newer less invasive mastectomy techniques gaining popularity, it is conceivable that techniques such as nipple/skin sparing mastectomy are being adopted in patients that have less favourable tumour characteristics than those in the studies in which these approaches were initially assessed ( 40 ).

Management of the Axilla

Management of the axilla has evolved in the last decade. Axillary nodal metastasis is a significant prognostic factor in breast cancer, influencing surgical and adjuvant treatment ( 41 , 42 ). While the surgical approach to the axilla has become increasingly conservative, the optimal management of the axilla continues to be a controversial topic.

Traditionally all patients proceeded to ALND irrespective of nodal status ( 43 ). ALND is associated with significant morbidity including lymphedema, impaired shoulder movement and arm sensation, resulting in a considerable impact on quality of life ( 44 , 45 ). The NSABP B32 trial randomized 5611 patients with clinically node-negative disease and a negative SLNB into two groups, ALND versus no further treatment. It found no significant difference in OS, DFS, or LRR between both groups. This demonstrated that ALND in those with a negative SLNB does not confer any survival benefit ( 46 ). SLNB was ultimately established as optimum standard for surgically assessing the axilla.

The extent of metastatic disease within the SLN is of prognostic importance. Nodal involvement is classified as macro-metastatic (>2mm), micro-metastatic (<2mm) or as isolated tumour cells (ITC). A systematic review found that the presence of micro-metastases is associated with decreased OS ( 47 ). The IBCSG 23-01 ( 48 ) and the AATRM 048 ( 49 ) trials, in which the majority of patients received adjuvant systemic therapy, demonstrated that ALND does not confer survival benefits in those with micro-metastatic nodal disease. As a result, many surgeons now omit ALND in patients with ITC or micro-metastatic disease on SLNB.

In cases of macro-metastatic disease, ALND has remained the standard of care ( 50 ). However, the ACOSOG Z0011 ( 51 ) questioned whether this represented overtreatment. In this phase 3 non-inferiority trial, 856 patients with T1 to T2 tumours with less than 2 positive SLNs were randomized to ALND versus no ALND, after breast conserving surgery (BCS), SLNB, and adjuvant whole-breast irradiation (WBI). The 5-year OS was higher in the SLNB group compared to those receiving ALND (92.5% versus 91.9% respectively). The 5-year DFS was also higher in the SLNB group (83.9%) compared to the ALND group (82.2%). While not significant, the 10-year LRR was 5.3% in the SLNB group, versus 6.2% in the ALND group. These results have been practice-changing for many surgeons. However, the Z0011 results have also added to the controversy surrounding optimal management of the axilla ( 52 – 54 ). This comes from the fact that Z0011 inclusion criteria were set at patients with tumours up to 5cm in size who underwent BCS and received WBI postoperatively. Furthermore, this study also failed to enrol the planned number of patients and thus did not have sufficiently high power to detect small differences between the groups.

As the approach to the axilla continues to evolve, the use of an oncologically safe alternative to ALND has been investigated. The AMAROS ( 55 ) trial included 4806 patients with T1 to T2, clinically node-negative invasive breast cancer and a positive SLNB. Patients were randomized to receive ALND or regional nodal irradiation (RNI). All underwent BCS followed by WBI, or mastectomy with or without chest wall irradiation. This trial provided evidence for regional nodal irradiation (RNI) as an alternative to ALND, with similar 5-year DFS and OS. The Edinburgh trials ( 56 ) randomized patients with N1 disease into ALND versus SLNB with RNI. This trial reported a significant difference in LRR, which was not seen in the AMAROS trial, concluding that there was no significant difference in OS between ALND and RNI. Now, several countries offer axillary radiotherapy as an alternative to ALND. The POSNOC trial aims to add to the evidence for radiotherapy in axillary management in patients with macro-metastatic nodal disease undergoing BCS and systemic therapy ( 57 ). Table 2 outlines the landmark RCTs in the surgical management of the axilla.

Table 2 Landmark RCT’s in the surgical management of the axilla.

Despite this shift towards a conservative approach, some studies have raised the possibility that failure to remove nodal disease could be harmful. Park et al. ( 59 ) suggest that the rate of axillary recurrence among patients with a positive SLNB who did not undergo ALND was 2.0% at 30 months versus 0.4% in those receiving ALND. Additionally, a retrospective review of 257,157 patients diagnosed with breast cancer in the Surveillance, Epidemiology, and End Results (SEER) database revealed decreased survival in patients with stage IIA or higher disease with increased number of positive nodes and increased ratio of positive to total nodes removed ( 60 ).

Considering the conflicting data, many ongoing trials aim to clarify the aforementioned studies and strengthen the rationale for omitting extensive axillary surgery. The SENOMAC trial ( 61 ) is comparing ALND versus no ALND after surgery with the primary endpoint being DFS at 5 years. Coming almost full circle, some clinicians are examining the utility of SLNB itself. For example there is a growing interest in omitting SLNB in early breast cancer patients with a clinically and radiologically negative axilla ( 62 , 63 ). However, other studies caution that despite a radiologically negative axilla there is a risk of high nodal burden axillary metastasis, particularly in T2 tumours. As such these patients should continue to undergo SLNB ( 64 ). Surgeons await the results from two RCTs, both the SOUND trial (Sentinel Node Vs Observation after Axillary Ultrasound) (NCT02167490) and the Intergroup-Sentinel-Mamma (INSEMA) trial (NCT02466737) which examine the role of AUS and SLNB in early breast cancer. It is possible that these trials will help negate surgical biopsy requirements in select patient groups, therefore advancing conservative axillary management further ( 65 , 66 ). Whether we can omit the ALND from the management of patients with breast cancer altogether remains to be seen. However, the trajectory to date has seen the management of the axilla evolve from a low threshold for performing ALND to an increasingly conservative one, consequently improving morbidity and patient outcomes.

Oncoplastic Surgery and Reconstruction

The primary aim of breast cancer surgery is complete tumour excision. However, improved cosmetic outcomes achieved with breast reconstruction continues to positively affect patient quality of life ( 67 ). This has given rise to the concept of oncoplastic breast surgery, which aims to provide an acceptable breast appearance while maintaining oncological effectiveness.

A variety of oncoplastic procedures have been described, and location of cancer within the breast is a major determinant of procedure choice ( 68 – 70 ). A 2014 meta-analysis found that patients treated with oncoplastic resections had a lower rate of positive margins (12% versus 21%) and a lower rate of re-excisions (4% versus 15%). Although patients undergoing oncoplastic surgery had a higher rate of completion mastectomies compared with those who underwent BCS (7% vs 4%), oncoplastic resections produced a higher satisfaction with breast appearance then standar BCS (90% vs 83%) ( 71 – 73 ). Furthermore, patients who underwent oncoplastic resections developed fewer complications (16% vs 26%) and decreased rates of local recurrence (4% vs 7%) at 3-5 year follow up, demonstrating that the long-term outcomes of oncoplastic surgery are comparable, if not better than standard BCS ( 71 ).

One of the first oncoplastic procedures that came into practice was the skin-sparing mastectomy (SSM), in which the breast parenchyma is excised, and most of the breast skin envelope is maintained ( 74 ). SSM has become a popular choice of procedure for patients with DCIS, early stage breast cancer as well as high-risk patients opting for prophylactic mastectomy due to its excellent cosmetic outcomes and acceptable oncological safety profile when compared to conventional mastectomy without reconstruction. Another commonly performed procedure is the nipple sparing mastectomy (NSM), used for high-risk women undergoing prophylactic surgery and also in select patients undergoing therapeutic mastectomy ( 75 ). This procedure preserves the nipple-areolar complex but removes major ducts from within the nipple lumen ( 76 ). A meta-analysis in 2018 demonstrated comparable 5 year DFS and LRR between NSM and SSM ( 77 ). Equally in a 2015 meta-analysis the OS, DFS, and LR rates of NSM were comparable to modified radical mastectomy and SSM ( 78 ).

Breast reconstruction can be performed using several techniques including an expander/implant and/or autologous tissues. Opinion within the surgical community regarding immediate breast reconstruction has evolved over time ( 79 , 80 ). When planning the optimal reconstructive option, surgeons must consider patient-specific factors such as likelihood of postoperative radiation, prior breast radiation as well as patient preference. Typically, delayed reconstruction is indicated when there is impaired perfusion of the skin flaps post-mastectomy or when post-mastectomy radiotherapy will be needed ( 81 ). However, the absolute contraindication of immediate autologous reconstruction due to the challenges posed by post-mastectomy radiotherapy is increasingly being questioned. While radiotherapy after immediate autologous reconstruction had been thought to have a detrimental impact on flap outcome, several systematic reviews have shown no significant differences in measurable postoperative complications when comparing irradiated versus non-irradiated reconstructions. As such, immediate DIEP flap reconstruction in patients who need post-mastectomy radiation is an acceptable treatment option ( 82 , 83 ). In the setting of inflammatory breast cancer where the presence of dermal lymphatic invasion often requires skin excision, a delayed reconstruction is more appropriate. However, often in cases of inflammatory breast cancer a decision is made not to proceed with reconstruction altogether.

Risk Reducing Surgery

A growing list of breast cancer susceptibility genes accompanies the ever-increasing amount of published clinical data. High-penetrance breast cancer susceptibility gene mutations associated with inherited breast cancer syndromes, such as BRCA1, BRCA2, PTEN (Cowden’s syndrome), TP53 (Li Fraumeni syndrome), STK11 (Peutz-Jeghers syndrome), CDH1 (hereditary invasive lobular breast-diffuse gastric cancer) and those with an associated family history account for approximately 10% of breast cancers ( 84 ). BRCA1/2 mutations occur in 3-4% of all patients with breast cancer and in 10% of those with triple negative breast cancer ( 85 , 86 ). Moderate penetrance breast cancer susceptibility gene mutations such as PALB2, CHEK2, ATM occur in 4-6% of breast cancer patients ( 85 ). Generally, it is advised that high-risk patients undergo more frequent screening, use of imaging modalities and consider prophylactic risk reducing surgery. Recently published guidelines offer recommendations on the management of breast cancer in patients with germline mutations in BRCA1/2, PALB2, CHEK2 and ATM ( 87 ).

Bilateral prophylactic mastectomy reduces the risk of breast cancer by 95% in patients with BRCA 1&2 mutations, and by 90% in those with a strong family history of breast cancer ( 88 ). Prophylactic mastectomy may be performed using many of the techniques described. Contralateral prophylactic mastectomy is considered for patients with a high lifetime risk for developing contralateral breast cancer, such as BRCA mutations, strong family history, or young patients with aggressive disease ( 87 ). Bilateral prophylactic salpingo-oopherectomy can reduce the risk of ovarian cancer by approximately 80% and the risk of all-cause mortality by 68% ( 89 ). Decisions regarding prophylactic mastectomy must be individualized for every patient. Benefits of the reduced anxiety relating to developing breast cancer must be balanced against risks of surgery, complications from reconstructive surgery as well as any potential adverse feelings relating to body image.

As family history breast clinics are further incorporated into routine clinical practice worldwide and as next-generation sequencing continues to become more accessible, it is expected that there will be an increase in the number of BRCA1/2 mutations diagnosed each year and at an earlier age. Thus, forward planning by policy makers for the provision of all aspects of patient management, including genetic counselling, surgery, radiotherapy, and oncological therapy, are required.

Novel Therapeutics

Interventional radiology (ir).

The use of IR-guided cryoablation as a minimally invasive technique to treat primary breast tumours is being explored ( 90 ). Through repetitive freezing/thawing cycles or rapidly decompressing argon gas, cryoablation results in cell injury and coagulative necrosis ( 91 ). Some studies have demonstrated feasibility of cryoablation for early breast cancer treatment ( 92 , 93 ). Ongoing trials are investigating complete response rate and local recurrence without subsequent surgery (FROST trial – NCT01992250; Ice3 trial – NCT02200715). This emerging modality may be most useful in those with significant co-morbidities who are less suitable for surgical resection. Other image-guided ablation techniques include radiofrequency ablation, microwave ablation, high-intensity focused ultrasound, laser ablation and irreversible electroporation ( 94 ).

Neoadjuvant Chemotherapy and Non Operative Strategies

Neoadjuvant treatments are increasingly being used in high-risk breast cancers such as triple negative and Her2 positive breast cancer. Neoadjuvant therapies are offered in patients at high risk of recurrence, in locally advanced disease, and to downstage the tumour to allow for BCS. Achieving a pathological complete response (pCR) is associated with improved event free survival and overall survival, particularly in triple negative and Her2 positive breast cancer ( 95 , 96 ).

Patients who achieve a partial or complete response pose a clinical dilemma in applying established surgery and radiotherapy treatment protocols. Patients who demonstrate a good clinical response to neoadjuvant treatment may benefit from de-escalation strategies in the adjuvant setting based on the degree of neoadjuvant response. Optimal methods to accurately detect a complete pathological response and the oncological safety in de-escalation strategies are currently the focus of a number of trials.

One such de-escalation strategy is to provide BCS for patients previously deemed unresectable or unsuitable for BCS. In an era of targeted therapy, increased rates of pCR in the breast have been observed. However advances in response to systemic therapy have not been matched with increased rates of BCS. It would be expected that those who achieve a complete response would be more likely to undergo BCS. However meta-analysis of RCT assessing eligibility for BCS following neoadjuvant chemotherapy found no association between rates of BCS and pCR ( 97 ). The inability to accurately detect viable tumour following neoadjuvant chemotherapy may contribute to the decision of the surgeon to perform a less radical procedure.

De-escalation of axillary management after neoadjuvant chemotherapy has also been explored following high rates of nodal pCR in patients who have histologically confirmed nodal disease ( 98 , 99 ). Due to the increased likelihood of false negative sentinel node biopsy following neoadjuvant chemotherapy, de-escalation of axillary clearance to sentinel lymph node biopsy alone following neoadjuvant chemotherapy in patients who were previously clinically node positive should only be considered if 3 or more negative nodes have been retrieved.

Whether surgery can be omitted in patients receiving neoadjuvant treatment who obtain a pCR, is under investigation. A trial (NCT02945579) is evaluating patients with HER2 positive or triple negative breast cancer who forgo surgery after systemic neoadjuvant therapy.

There is currently no evidence to suggest that avoidance of surgery in patients who have a pCR is oncologically safe. Analysis of the NSABP B-18 and B-27 trials observed LRR of 6-9% in patients who had a pCR following neoadjuvant chemotherapy and BCS or mastectomy ( 100 ).

Until such a time as the accuracy of imaging and core needle biopsies can reliably determine pCR surgery with histological assessment of the resected specimen is likely to remain a corner stone of effective treatment, accurate assessment of pCR, and reduction of local regional recurrence.

Future Perspective on Breast Cancer Surgery

Surgical innovation continues to drive advances in the management of breast cancer. Artificial intelligence (AI) technology and machine learning algorithms applied to diagnostic imaging and analysis of large clinical and genomic datasets in predicting response to treatment have been shown to improve patient outcomes ( 101 – 104 ). Once healthcare practitioners have overcome the fear of the unknown and data scientists and AI experts become more incorporated into healthcare, the future of surgical breast cancer management may change rapidly. Capabilities for storing vast amounts of data for imaging analysis can be applied to a multitude of areas from digital pathology to surgical planning. Digitization of breast cancer pathology with whole slide imaging has enabled the use of artificial intelligence machine learning algorithms to be applied to digital pathology. These advances in computer aided diagnostics have the potential to replace some of the expensive multi-gene assays ( 105 , 106 ). Machine learning for image analysis will act as an adjunct to enhance human reporting, increase accuracy, and improve outcomes by predicting the likelihood of recurrent disease and dictating the optimum surgical intervention. AI have also been used to aid surgical planning using MRI based 3D reconstructions of the tumour within the breast ( 107 ).

Technological advancements in the surgical management of non-palpable breast lesions such as wire-free radar technology to provide real-time surgical guidance during breast surgery have demonstrated efficacy and are oncologically safe ( 108 , 109 ). The emergence of imaging and probe-based devices to detect differences between normal and cancerous tissue have the potential to improve margins, reduce re-operation rates and avoid current labour-intensive intraoperative margin assessment techniques such as frozen section and specimen radiology. The intelligent knife (iKnife) utilizes rapid evaporative ionisation mass spectrometry of aerosol generated by electrocautery of tissue. This technique provides a rapid and effective method for identification and characterization of neoplastic tissue, guides resection in vivo and improves the quality of the surgical resection ( 110 , 111 ). A future surgical model may include SLNB and axillary dissection with real time diagnosis for presence of axillary disease.

Advances in the surgical management of breast cancer have favoured an increasingly conservative approach. This article reviews the current evidence in surgical management of early-stage breast cancer, discusses recent trends in surgical practice for therapeutic and prophylactic procedures and provides commentary on implications associated with these trends.

Author Contributions

Literature research – SK, MF. Manuscript Preparation – SK, MF. Manuscript Review – SK, MF, AH. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: breast cancer, breast cancer surgery, mastectomy, axilla, breast conserving therapy

Citation: Keelan S, Flanagan M and Hill ADK (2021) Evolving Trends in Surgical Management of Breast Cancer: An Analysis of 30 Years of Practice Changing Papers. Front. Oncol. 11:622621. doi: 10.3389/fonc.2021.622621

Received: 28 October 2020; Accepted: 19 April 2021; Published: 04 August 2021.

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Copyright © 2021 Keelan, Flanagan and Hill. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Michael Flanagan, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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The original article was published in Breast Cancer Research 2024 26 :69

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Higher Risk of Depression After Total Mastectomy Versus Breast Reconstruction Among Adult Women With Breast Cancer: A Systematic Review and Metaregression

Affiliations.

• 1 International Doctoral Program in Nursing, Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
• 2 International Doctoral Program in Nursing, Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
• 3 Department of Public Health, National Cheng Kung University, Tainan, Taiwan. Electronic address: [email protected].
• 4 Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
• 5 Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Public Health, National Cheng Kung University, Tainan, Taiwan; Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: [email protected].
• PMID: 33541834
• DOI: 10.1016/j.clbc.2021.01.003

This systematic review with a meta-regression was conducted to determine the risk of depression after mastectomy compared to breast reconstruction among women with breast cancer 1 year after surgery. A literature search was conducted according to PRISMA guidelines using 4 databases: Medline (Ovid), Embase, Cinahl, and the Cochrane Library for the period January 2000 to March 2019. Studies that measured the status of depression within 1 year and immediately after surgery were included. Outcomes related to depression were analyzed by using a pool of event rates and a risk ratio of 95% confidence interval (CI), P value, and a fitting model based on the results of a heterogeneity test of mastectomy and BR. The statistical analysis was conducted using Comprehensive Meta-analysis 3.0 software. Nine studies met the inclusion criteria. There were 865 cases of mastectomy only, with a 22.2% risk of depression (95% CI, 12.4-36.2). In 869 women who underwent BR, the risk of depression was 15.7% (95% CI, 8.8-26.2). The depression risk ratio for mastectomy compared to BR was 1.36 (95% CI, 1.11-1.65). Patients with delayed reconstruction exhibited lower levels of depression (risk ratio 0.96, 95% CI 0.57-1.01). The Beck Depression Inventory (BDI) scale showed high sensitivity, and the Hospital Anxiety Depression Scale (HADS) with a cutoff of > 7 could measure even low to moderate depressive symptoms. One in 4 women with breast cancer had symptoms of depression after mastectomy; both surgeries were associated with depression in women 1 year after surgery. Our results will permit the development of proactive treatment plans before and after surgery to mitigate risk and prevent depression through the use of sensitive depression scales like BDI.

Keywords: Breast cancer; Delayed breast reconstruction; Depression; Immediate breast reconstruction; Total Mastectomy.

Copyright © 2021. Published by Elsevier Inc.

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• Cancer epidemiology
• Risk factors

Breast cancer (BC) is one of the major public health challenges worldwide. Studies that address the new evidence on trends of BC are of great importance for preventing and controlling the occurrence and development of diseases and improving health. The aim of this study was to analyze the outcomes for the global burden of disease (GBD), incidence, deaths, and risk factors for BC from 1990 to 2019, and predict the GBD of BC until 2050 to inform global BC control planning efforts. In this study, the results show that the regions with low levels of socio-demographic index (SDI) will have the largest disease burden of BC in the future. The leading global risk factor for death attributable to BC in 2019 was metabolic risks, followed by behavioral risks. This study supports the worldwide urgent need for comprehensive cancer prevention and control strategies to reduce exposure, early screening, and improve treatment to effectively reduce the GBD of BC.

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Introduction.

Breast cancer (BC) is a most common malignant tumor, and its global burden of disease (GBD) has become one of the important factors that endanger the health of the world population, especially the health of women 1 . The global BC statistics report shows that in 2020, there will be 2.261 million new cases and 685,000 deaths worldwide, and BC has become the number one malignant tumor in the world 2 . Although some cancer cases cannot be prevented, governments can develop a range of health interventions to minimize exposure to known cancer risk factors, such as environmental factors, lifestyle behaviors, dietary habits, metabolic factors, etc 3 . Therefore, understanding the relative contributions of modifiable risk factors to the GBD of BC and their long-term trends is critical to inform local and global cancer control efforts.

Global Health Data Exchange provides two important research tools (GBD Comparison Tool and GBD Results Tool) that have been open sourced to quantify GBD, assessing GBD by age group, sex and time (1990 to 2019) in countries around the world), attributed to a wide range of modifiable risk factors 4 . GBD 2019 is the latest iteration of the GBD study, which provides an opportunity to assess the global cancer burden attributable to risk factors. Previous studies assessed the global, regional, and national burden of breast cancer until 2017 5 , 6 , 7 , 8 , 9 . A recent study 10 evaluated the GBD of female BC from 1990 to 2019 and predicted the GBD of female BC in 2035. However, these studies know little about the global cancer burden attributable to metabolic, behavioral, diet, physical activity factors and its more longer-term future forecasts to 2050.

In this study, we report for the first time the GBD for BC attributable to a comprehensive inventory of metabolism, behavior, diet, and physical activity from 1990 to 2019, using breast cancer incidence, deaths, and risk factor results. Furthermore, this study provides a new perspective on the attributable cancer burden by estimating the risk-attributable cancer burden at global levels using incidence and deaths.

Global burden of disease and temporal trends of breast cancer

To assess the global GBD and changing trends of BC, the incident cases, death cases and ASR of BC in 1990 and 2019 were calculated, and the estimated annual percentage change (EAPC) was used to demonstrate the temporal trends from 1990 to 2019. The global GBD and temporal trends of BC are presented in Supplementary Tables  1 and 2 . Globally, the incident cases of BC increased from 876,990 in 1990 to 2,002,350 in 2019, and the EAPC for incidence increased by an average 0.33% per year. Although the death cases of BC in 2019 is higher than in 1990 worldwide, the EAPC for deaths decreased by an average 0.56% per year. In terms of gender, the number of cases and ASR of women are higher than that of men, regardless of morbidity and death. However, it is worth noting that the EAPC for incidence in men increased by an average 0.91% per year, which is higher than the woman with 0.36%. And the EAPC for deaths in different gender population both gradually decreased. Compared with other SDI regions, the incident cases, death cases and ASR of BC in high SDI regions were at a higher level. However, it is exciting to note that the EAPC for incidence began to decline in high SDI regions, and the EAPC for deaths also decreased the most in this group. In the other hand, we also observed a fast increase in the EAPC for incidence in the middle SDI regions and the EAPC for deaths in the low SDI regions. Further observation of the GBD and temporal trends of 21 GBD regions found that the highest incident cases and ASR for incidence of BC is in East Asia region, and the largest decline for EAPC is in Central Asia region. Moreover, Western Sub-Saharan Africa is the only region where EAPC for incidence continues to grow. Western Europe, Oceania and High-income North America are the region with higher breast cancer deaths in 1990, but by 2019, only the Oceania region was found to still be at relatively high levels. The EAPC for deaths in the Western Sub-Saharan Africa region increased fast, but High-income North America, Australasia and Western Europe regions decreased more obviously.

Figures  1 and 2 show the GBD of BC incidence and mortality for 204 countries and territories. As shown, the countries with the highest incidence and deaths of ASR in 1990 were concentrated in high-income countries (Figs.  1a and 2a ). However, the top 2 countries with the highest incidence and deaths of ASR in 2019 are not high-income countries, such as Lebanon and Solomon Islands with the highest incidence (Fig.  1b ) and Pakistan and Solomon Islands with the highest death (Fig.  2b ). Subsequently, we further analyzed global changes in cancer case (Figs.  1c and 2c ) and EAPC (Figs.  1d and 2d ) to better indicate temporal trends in GBD. From the perspective of changes in cancer cases, only 2 countries have seen a decline in incidence, while 72 countries have seen a decline in deaths. Among them, 52 countries with an increase for incidence of more than 300%, but only 3 countries had an increase for deaths of more than 300%, and the largest increase was both in the Solomon Islands.

Global GBD and temporal trends of BC incidence in 204 countries or territories. ASR: age standardized rate; BC: breast cancer; EAPC: estimated annual percentage change; GBD: global burden of disease. ( a ) The ASR per 100,000 people in 1990; ( b ) The ASR per 100,000 people in 2019; ( c ) The change in cancer cases; ( d ) EAPC in different countries or territories.

Global GBD and temporal trends of BC deaths in 204 countries or territories. ASR: age standardized rate; BC: breast cancer; EAPC: estimated annual percentage change; GBD: global burden of disease. ( a ) The ASR per 100,000 people in 1990; ( b ) The ASR per 100,000 people in 2019; ( c ) The change in cancer cases; ( d ) EAPC in different countries or territories.

Supplementary Fig.  1 combines EAPC for incidence and deaths data in a hierarchical cluster analysis to identify countries with similar annual growth rates in incidence and deaths. As shown in the multimedia appendices, 35 countries (or territories) were cluster into the significant increase group, including the Northern Mariana Islands, Taiwan (Province of China), Netherlands, Germany, Viet Nam, Gambia, etc . A total of 39 countries (or territories) were categorized into the minor increase group, including United States of America, United Kingdom, Pakistan, Canada, etc . Another 120 countries (or territories) were grouped into the remained stable or minor decrease group, including China, Japan, France, Mexico, and Solomon Islands. The remaining 10 countries (or territories) were categorized into the significant decrease group, including Turkmenistan, Uzbekistan, Puerto Rico, Kazakhstan, Bahrain, Colombia, Singapore, Maldives, Chile.

Global burden of disease of breast cancer attributable to risk factors

The results of GBD of BC attributable to the risk factors were shown in Fig.  3 and Supplementary Figs.  2 and 3 . As revealed in the Figure, the leading risk factor in terms of attributable BC deaths was metabolic risks worldwide, which accounted for 31.98% in 1990, and has a gradual increasing trend in 2019, accounting for 46.87%. Alcohol use, tobacco, dietary risks, and low physical activity were the next greatest risk factors. The percentage of BC deaths due to metabolic risks was significantly heterogeneous all over the world, with the highest percentage observed in Oceania region (55.48% in 1990 and 63.76% in 2019), followed by Southeast Asia region (47.34% in 1990 and 63.69% in 2019). The largest increase in the percentage for BC deaths due to the metabolic risks from 1990 to 2019 are Southern Sub-Saharan Africa (17.66%), South Asia (17.29%), Andean Latin America (16.59%), Southeast Asia (16.35%) regions. At the same time, we also observed a gradual decrease in the percentage of BC deaths due to behavioral risks such as such as alcohol use and tobacco. Dietary risks and low physical activity have remained relatively stable over the past 20 years. When we assessed the time trends of attributable risk factors at the SDI level, we found that the most increase in the percentage for BC deaths due to the metabolic risks from 1990 to 2019 are in the middle (14.42%), low-middle (14.41%) and middle-high (13.29%) SDI areas. Multimedia Appendix 2 shows the two metabolic risks attributable to breast cancer death. As shown in the figure, the global and low, middle-low and high SDI regions accounted for half and half percentage of BC deaths due to high fasting plasma glucose and high body mass index, but the fasting plasma glucose in the middle, middle-high SDI region was very high, accounting for 70.10%~ 84.62%. Furthermore, the proportion of low, low-middle, and middle SDI areas attributed to the high body mass index is increasing, especially in the low-middle SDI areas, from 42.65% in 1990 to 54.70% in 2019.

GBD of BC attributable to risk factors in 1990 and 2019. BC: breast cancer; GBD: global burden of disease; SDI, socio-demographic index.

Factors influencing the estimated annual percentage change in the global burden of disease

To better explain GBD in BC, we analyzed influencing factors that may affect EAPC, including ASIR, ASDR, and HDI (which can be used as an indicator of the level and availability of medical care in each country) (Fig.  4 ). As illustrated in the Figs.  4a,b , a significant negative correlation was found between EAPC and ASIR, ASDR in 1990 ( r  = −0.607, −0.583; P all  < 0.001). In contrast, this negative correlation in 2019 gradually weakened or disappeared. EAPC had a weak negative correlation with ASIR ( r  = −0.152; P  = 0.030) in 2019, but a positive correlation with ASDR ( r  = 0.315; P <  0.001). Figure  4c,d show the correlation between the EAPC and HDI. As revealed in the figure, whether in 1990 or 2019, the relationship between EAPC and HDI is not a simple linear correlation, on the contrary it is more like a “parabola”. when the HDI was limited to below 0.50 in 1990 or 0.55 in 2019, a significant positive correlation was found between EAPC for incidence and deaths and HDI. In contrast, for a HDI above 0.50 in 1990 or 0.55 in 2019, the positive association gradually disappeared, and EAPC for incidence and deaths has a significant negative correlation with HDI in 1990 ( r  = −0.312, −0.548; P all  < 0.001) and 2019 ( r  = −0.300, −0.582; P all  < 0.001).

Factors Influencing EAPC in the GBD. ASR: age standardized rate; ASIR: age standardized incidence rate; ASDR: age standardized death rate; BC: breast cancer; EAPC: estimated annual percentage change; GBD: global burden of disease; HDI: human development index. ( a ) The correlation between EAPC and ASR in 1990. ( b ) The correlation between EAPC and ASR in 2019. ( c ) The correlation between EAPC and HDI in 1990. ( d ) The correlation between EAPC and HDI in 2019.

Future forecasts of global burden of disease in breast cancer

Figure  5 show the future forecasts of GBD in BC. As illustrated in the Fig.  5a,b , the ASR of BC incidence in the world will gradually increase. It is estimated that by 2050, the ASR of BC incidence in female will be 59.63 per 100,000, an increase of 32.13% compared with 2019; the ASR of BC incidence in male will be 0.65 per 100,000, an increase of 1.74% compared with 2019. Subsequently, we also estimated the ASR of global BC deaths from 2020 to 2050 (Fig.  5c,d ). Over time, the ASR of BC death in female increased slightly, but the ASR of BC deaths in male gradually decreased. It is estimated that by 2050, the ASR of female BC deaths will be 16.42/100,000, an increase of 4.69% compared with 2019; the ASR of BC deaths in male will be 0.26 cases per 100,000, a decrease of 19.84% compared with 2019. According to the United Nations world population forecast data, there will be 4,781,849 incident cases (4,714,393 women and 67,456 men) and 1,503,694 death cases (1,481,463 women and 22,231 men) of BC in the world in 2050.

Future Forecasts of GBD in BC. ASIR: age standardized incidence rate; ASDR: age standardized death rate; BC: breast cancer. ( a ) The ASIR per 100,000 for male; ( b ) The ASDR per 100,000 for male; ( c ) The ASIR per 100,000 for female; ( d ) The ASDR per 100,000 for female.

Breast cancer incidence burden

Our analysis found that the global incident cases of BC increased from 876,990 in 1990 to 2,002,350 in 2019, a total increase of 1.28 times. This is an increase of another 5 percentage points compared to the 2017 GBD data for BC 11 , which showed that the global incident cases of BC increased by 123% between 1990 and 2017. Although we have seen a sharp increase in the BC incident cases worldwide in the past 20 years, the ASR has not shown a trend of rapid growth. And this slow growth trend is also confirmed by our EAPC results and other study 11 , which also found that from 1990 to 2017, the incidence of breast cancer worldwide increased by 123%, but the change in ASR was not obvious. Previous study 12 has found that the changes in the number of BC cases are largely attributable to population growth and aging. This seems to explain the findings in this study well, since our study only found a significant increase in the incident cases of BC, not ASR. It suggests that reducing the global population may be one of the key factors in reducing BC incidence.

For the gender, we saw an absolute predominance of women, which is logical, but it is worth noting that the EAPC for incidence in men is significantly higher than that in women and continues to increase at an average rate of 0.91% per year. These results suggest that we should not ignore men in the health monitoring of BC in the future, especially for those who have bad behavior factors, such as smoking, alcohol use. The latest study 1 found that tobacco is the main risk factor of cancer for male, followed by alcohol use, dietary risks and air pollution.

SDI is a composite index calculated based on the total fertility rate of women under the age of 25, the per capita lagged distribution income and the average education level of individuals aged 15 and above 13 . Our results showed that the higher the SDI level, the higher incident cases and ASR of BC, but the EAPC did not appear consistent. On the contrary, in the meddle-high and high SDI regions, the EAPC of BC incidence was significantly reduced, especially in the high SDI region even showed negative growth. These findings were also confirmed by further association analysis, and it was found that EAPC showed a significant negative correlation with ASIR. One possible explanation is that the ASR of BC incidence in these regions was higher in the past, with limited room for increase. Furthermore, due to the general increase in the education level of the population in these areas, people’s awareness of health has been continuously strengthened, which has limited the growth of BC to a certain extent. However, it is worth noting that in low, low-middle, and middle SDI regions, changes in the ASR and EAPC due to population growth and due to the global rise in SDI levels, they are re expected to impose increasing burdens on individuals and societies.

From the analysis of countries or regions, the countries with high ASR of BC incidence 20 years ago were mainly concentrated in high-income countries (such as the United States, New Zealand and the Netherlands), but in 2019, some low-income countries (such as Solomon Islands, Lebanon) rapidly occupy the position of high ASR incidence. These results support our previous hypothesis that low, low-meddle, and middle SDI regions are projected to impose increasing burdens on individuals and society. Furthermore, East Asia is the region with the highest ASR of BC incidence, sub-Saharan Africa is the only region where the EAPC of BC continues to grow, and Solomon Islands is the only country where EAPC has increased by more than 6%. These countries and regions should be the focus of future BC disease burden monitoring.

Further GBD future forecasts for BC demonstrated that that from 2020 to 2050, the global BC incidence and total incidence will increase year by year. Therefore, how to control modifiable risk factors and reduce the incidence of BC becomes the key to alleviating GBD of BC.

Breast cancer deaths burden

ASR for deaths, as one of the commonly used indicators in disease burden research, can measure the level of risk to the population from the perspective of life 9 . Our study demonstrated that the global death cases of BC in 2019 (700,660 cases) was higher than in 1990 (380,910 cases). There will be 1,503,694 death cases (1,481,463 women and 22,231 men) of BC in the world in 2050. These results suggest that the GBD from breast cancer deaths will remain severe for some time to come. The incidence of BC is dominant in females, so the relatively higher death rate in females may be related to the higher incidence of BC in females than in males. Previous studies 9 , 11 have shown that high-income countries such as North America and Western Europe have a higher GBD of BC due to death. Our GBD study based on 1990 also came to a similar conclusion. But what is exciting is that by 2019, the ASR for deaths in high-income countries such as North America and Western Europe has gradually declined the most obvious in all countries. These findings were also confirmed by the results of death cases and death ASR in different SDI index countries and the significant negative association between HDI and EPAC. A logical explanation is that the application in widespread mammography for early-stage BC diagnosis in high-income and high-SDI countries 7 , 14 and improved treatment facilities in terms of chemotherapy, radiation therapy, and targeted approaches may be the underlying reasons for the decline in BC mortality in these countries. In addition, our study also found that the growth of EAPC for deaths was particularly rapid in low and low-medium SDI regions and in sub-Saharan Africa. Possible solutions behind this growing trend are access to widespread mammograms, improved BC awareness, increased exercise and greater access to healthcare, among others. It is worth noting that in low-income countries, individuals suffering from severe illnesses may opt to discontinue their treatment because of the considerable financial burden it places on their families. This decision can lead to a rapid deterioration of their condition and ultimately hasten their demise, a phenomenon known as “near-suicide.” Research indicates that as the severity of the illness increases, patients are more likely to forego treatment due to familial responsibilities 15 . These findings underscore the importance of providing accessible and affordable healthcare for individuals dealing with serious illnesses.

Risk factors attributable to breast cancer burden

The latest research evidence 1 shown that 44.4% of global cancer deaths and 42.0% of global cancer disability-adjusted life years can be attributed to GBD 2019 estimated risk factors. Our study demonstrates that the major risk factor globally attributable to BC deaths is metabolic risks. High body mass index and high fasting glucose have also been identified as potential risk factors attributable to BC deaths 11 , and our study found that the proportion of contribution of the two risk factors was quite different in various SDI regions of the world. In most countries with high SDI, the growth rate of national wealth is also the fastest, and the growth rate of national wealth is often proportional to the increase in body weight 16 . Our study did not observe a significant increase in the proportion of BC death risk attributable to high body mass index in high-income countries, which may be related to the traditional low-calorie diet 17 and high physical activity in the part of countries, such as walking 18 . Conversely, the proportion of BC deaths attributable to high body mass index is increasing in low, low-middle SDI regions. It suggests that the body weight control is the key to reduce the risk of BC disease in the future, in these regions, especially in low-middle SDI region. However, glycemic control may be more important for middle and middle-high SDI regions, where a very high proportion of BC deaths are attributable to high fasting glucose.

Alcohol use is one of the important risk factors for BC death 11 , and a pioneering study 19 has revealed a possible dose-response relationship between alcohol consumption and BC. Our study found that the proportion of disease burden of BC deaths attributable to alcohol use gradually decreased in meddle-high and high SDI countries, which may be very much related to the significant decline in the prevalence of daily alcohol consumption globally 20 . These results may also better explain why the incidence and deaths of BC in high-income countries such as North America and Europe have gradually decreased, despite high-calorie, high-metabolic diets.

The GBD 2019 Study shows that smoking remains the leading cause of cancer death and health loss worldwide 1 . Our study found that the proportion of BC disease burden attributable to smoking decreased gradually over time in low, low- middle, and middle SDI regions, which may be related to the decline in smoking prevalence in these regions. Because previous study 21 has shown that smoking rates decline with the lower SDI. In addition, our study indicates that the dietary risk and low physical activity also play a role in the burden of BC disease. Therefore, reducing the global burden of breast cancer requires a comprehensive cancer prevention and control strategy. On the one hand, reduce the incidence and death of breast cancer by controlling adverse metabolic risks and behavioral risks (such as alcohol use, tobacco, dietary risk, low physical activity); on the other hand, by promoting mammography for early diagnosis of breast cancer, and improvements in effective treatments to effectively reduce the global burden of disease.

Strengths and limitations

To our knowledge, this GBD-based study is the largest effort to date to reveal global BC incidence and deaths, determine the global cancer burden attributable to the most relevant risk factors, and predict the future burden of BC. The study will help to enrich the research evidence of global BC risk and attributable disease burden 11 , 22 , 23 , 24 , 25 , which is of great important to prevent and control the occurrence and development of BC and improve health. However, our study also has limitations. First, some countries (or territories) do not have population-based cancer registries, leaving an important source of data for estimating cancer burden missing. Second, the GBD2019 only provides some behavioral risks (such as tobacco, alcohol use, dietary risks and low physical activity) and metabolic risks (including high fasting glucose and high body mass index) that can be used for further research 26 , are important for a comprehensive assessment of the burden of breast cancer attributable to risk factors. Finally, the disability-adjusted life years, as an index that can simultaneously consider premature death from disease and health loss from disability, has received increasing attention in the field of international cancer disease burden evaluation 27 , and this study focuses on diseases caused by BC incidence and deaths burden.

Moreover, data sharing, a practice that enhances research integrity and transparency, facilitating peer validation and enabling further exploration of the study’s findings, offers valuable resources for scientific research and evidence-based policymaking, particularly relevant to developing countries 28 , 29 . In this sense, our research has significant meaning, because all data available free of charge. Our data provide a rigorous and comparable measure of the global disease burden of breast cancer, all freely downloadable, and can be used by policymakers in the future to generate the evidence they need on how to allocate resources to best improve the population Health makes informed decisions. Nonetheless, it is worth noting that our findings may be delayed as they reflect past disease burden. While our analysis provides valuable insights into the historical trends of breast cancer, predicting future trends necessitates confirmation by more recent data.

Overall, our study provides some evidence that regions with low levels of SDI will have the largest disease burden of breast cancer in the future. Metabolic risk factors increased the most from 1990 to 2019, compared with the behavioral factors. The findings of this study may be of great value for preventing and controlling the incidence and deaths of BC, as well as for improving the health of population. Furthermore, our study results may aid decision makers in formulating more reasonable and effective preventive health policies, and solutions for BC, and related health inequalities.

Study design

In this study covering data of GBD on incidence, deaths, and their temporal trends in 204 countries or territories and 21 regions from 1990 to 2019, different changing trends of BC burden were observed, with significant differences by sex, region, country, and sociodemographic index. The logical flowchart of this study is shown in Supplementary Fig.  4 .

Data sources

Annual incident cases, age standardized incidences and deaths of BC from 1990 to 2019, by sex, region, country, and risk factors (metabolic risks, dietary risks, tobacco, alcohol use and low physical activity) were obtained from the GBD 2019 through the Global Health Data Exchange (GHDx) query tool ( https://ghdx.healthdata.org/gbd-2019 ).

To create the source dataset, we follow a procedure. First, we access the data acquisition interface of the database and click on the “query tool” hyperlink located under the “GBD Results Tool” menu. This leads us to the data retrieval interface where we have the option to select different GBD evaluation options from the “GBD Estimate” drop-down menu. By default, cause of death or injury is selected. Next, we can choose from a variety of disease evaluation indicators such as morbidity, prevalence, mortality, and disease burden, including disability-adjusted life years, from the “Measure” drop-down menu. We can also select different measurement indicators like number, percent, and rate from the “Metric” drop-down menu. The “Cause” drop-down menu provides an extensive list of common causes such as tumor, high blood pressure, and diabetes, among others. Similarly, the “Location” drop-down menu displays all the countries and regions in the world which are categorized in great detail, including China (national level) and East Asia (regional level). For some countries like the United States and the United Kingdom, intra-country state or provincial level data is also available although this feature is not currently available for China. Moreover, we can filter data by age and sex using the “Age and Sex” drop-down menu, while the “Year” drop-down menu allows us to choose a time range between 1990–2019. GBD 2019 is the most up to date and ongoing global collaboration, and all epidemiological data are available as open source. Simply enter your desired query in the search box above and click “Search” to retrieve the relevant information. Alternatively, you may choose to directly download the CSV file by clicking on the “Download CSV” button.

Data records

A total of 204 countries or territories and 21 regions were selected in this study. The human development index (HDI) data at the national level were collected from the United Nations Development Programme ( https://hdr.undp.org/data-center/human-development-index#/indicies/HDI ). Rates in this study are reported per 100,000 people, and age-standardized rates are calculated based on GBD world population standards 30 . Some of the results were provided by the sociodemographic index (SDI) to describe differences in GBD of BC. The quintiles of the SDI index are used to define low (~20), low-middle (~40), middle (~60), middle-high (~80) and high (~100) SDI countries in 2019 27 . The global population forecast data for 2017–2100 were obtained from the Institute for Health Metrics and Evaluation ( https://ghdx.healthdata.org/record/ihme-data/global-population-forecasts-2017-2100 ). The data supports this finding have recorded in the Figshare 31 ( https://doi.org/10.6084/m9.figshare.22787405 ). The document “GBD for BC.xlsx” comprises six main worksheets. The first worksheet, named “BC_nation,” is primarily utilized to analyze the country’s morbidity and mortality related to BC, enabling quantification of this data. The following worksheets - “BC_region,” “BC_region_SDI,” and “BC_region_SEX” - are used to examine the morbidity and mortality of BC quantified by region, SDI, and sex. To assess trends in BC incidence and mortality, an estimation of the change in cancer cases from 1990 to 2019, along with the EAPC and its 95% confidence interval, are used. Finally, the “BC_percent” worksheet focuses on estimating the cancer burden attributable to risk factors.

Data analysis

Referring to previous literature report 32 , the age-standardized ratio (ASR) and its 95% uncertainty interval was used to quantify the incidence and deaths of BC by time, sex, region, country and SDI. Then, the changes in cancer cases, the estimated annual percentage change (EAPC) and its 95% confidence interval from 1990 to 2019 was used to assess the incidences and deaths trend of BC. Finally, we combined EAPC data for incidences and deaths to perform hierarchical cluster analysis to identify countries with similar annual increases in incidences and deaths. All countries were divided into 4 groups, including minor increase, remained stable or minor decrease, significant decrease, and significant increase.

GBD 2019 includes three categories of attributable risks, such as environment or occupation risks, behavior risks and metabolism risks. We first identified the BC risk factors with convincing or likely causal evidence based on World Cancer Research Fund criteria. Then, the proportion of cancer-specific burden attributable to each risk factor was calculated in different year, region, country and SDI. Finally, temporal trends of attributable risk factors were assessed at the SDI level.

We selected two-time nodes, 1990 and 2019, and calculated the age-standardized incidence rates (ASIR) and age-standardized deaths rates (ASDR) at the country level. Then, HDI, ASIR, ASDR were selected as the candidate indicators to determine the influencing factors of EAPC by correlation analysis.

Considering that the incidence and mortality rates of different sexes are different, in this study we separately predicted the incidence and deaths rates of men and women from 2020 to 2050 to assess the future GBD of BC. This GBD forecasts is primarily based on the Global Population Forecasts 2017–2100 data and age-standardized BC incidence and deaths data from 1990 to 2019.

All statistical analysis of data were performed using the R Project for Statistical Computing (version 4.2.2; R Core Team). We used the ASR and EAPC to quantify the BC incidence and deaths trends. Constituent ratios were used to evaluate the cancer burden attributable to risk factors. Pearson correlation analysis was used to determine the association of HDI, ASIR, ASDR with EAPC. For the future forecasts of GBD in BC, we used the BACP package. A threshold of P value less than 0.05 was set to determine the significant differences.

Usage Notes

Our data and code are freely available as open source. The analysis codes presented in the article were written using the R language. To conduct your own analysis, you will need to first install the necessary environment for R, including packages such as dplyr, ggplot2, ggsci, factoextra, ggmap, rgdal, maps, devtools, and others. Moving forward, these data can be utilized to examine the disease burden of breast cancer and its changing trends, categorized by time, sex, region, country, and SDI. Additionally, if you intend to analyze other disease burdens apart from breast cancer, our open-source R language code is also well-suited for your needs.

Data availability

The data supports this finding can be accessed from the Figshare 31 ( https://doi.org/10.6084/m9.figshare.22787405 ). The “Date.xlsx” file contains separate sheets that provide pertinent metadata for assessing the incidence and mortality rates of breast cancer based on various factors such as time, gender, region, country, and socio-demographic index (SDI). In addition to this information, the document also includes data on the World population age standard, the HDI of different countries in 1990, and Global Population Forecasts spanning from 2017 to 2100.

Code availability

All R code supporting the conclusions of this study can be accessed and downloaded via Github 33 ( https://doi.org/10.5281/zenodo.7915783 ). The main computational tools used in this study are R language based. The scripts used in this study include “GBD_Incidence_region.R,” which calculates incident cases, deaths, ASR, and EAPC for BC worldwide during 1990 and 2019. Another script, “GBD_Incidence_map.R” is employed to generate visualizations of BC incidence and mortality using GBD data from 204 countries and regions around the world. Additionally, “GBD_cluster.R” was used to perform hierarchical cluster analysis to identify countries with similar annual increases in BC incidence and mortality. To calculate the percentage of major risk factors globally attributable to BC mortality, “GBD_Percent.R” was utilized. The correlation between EAPC and ASIR, ASDR, and HDI was analyzed using “GBD_COR.R”. Finally, “Global_BAPC_prediction.R” was implemented to predict the future burden of BC using GBD data.

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Acknowledgements

We highly appreciate the works by the Global Burden of Disease Study 2019 collaborators. This work was supported by the National Key Research and Development Program “Precision Medicine Initiative” of China (Grant 2017YFC0907301).

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These authors contributed equally: Yuyan Xu, Maoyuan Gong.

Authors and Affiliations

Guizhou Medical University, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education & Guizhou Provincial Engineering Research Center of Ecological Food Innovation & School of Public Health, Guiyang, 550025, China

Yuyan Xu, Maoyuan Gong, Yang Yang & Qibing Zeng

The Affiliated Hospital of Guizhou Medical University, Department of Breast Surgery, Guiyang, 550004, China

Yue Wang & Shu Liu

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Y.X. and M.G. performed data collection and analysis, results visualization, and wrote the manuscript. Y.W. and Y.Y. made contributions to data acquisition and analysis. S.L. and Q.Z. made significant contributions to the conceptualization, methodology, data analysis, supervision, validation, and writing– review & editing of the study. Final manuscript read and approved by all authors. Correspondence to Shu Liu and Qibing Zeng.

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Xu, Y., Gong, M., Wang, Y. et al. Global trends and forecasts of breast cancer incidence and deaths. Sci Data 10 , 334 (2023). https://doi.org/10.1038/s41597-023-02253-5

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Advances in Breast Cancer Research

A polyploid giant cancer cell (PGCC) from triple-negative breast cancer.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat breast cancer. They are also looking at how to address disparities and improve quality of life for survivors of the disease.

This page highlights some of what's new in the latest research for breast cancer, including new clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Breast Cancer

Breast cancer is one of a few cancers for which an effective screening  test, mammography , is available. MRI ( magnetic resonance imaging ) and  ultrasound  are also used to detect breast cancer, but not as routine screening tools for people with average risk.

Ongoing studies are looking at ways to enhance current breast cancer screening options. Technological advances in imaging are creating new opportunities for improvements in both screening and early detection.

One technology advance is 3-D mammography , also called breast tomosynthesis . This procedure takes images from different angles around the breast and builds them into a 3-D-like image. Although this technology is increasingly available in the clinic, it isn’t known whether it is better than standard 2-D mammography , for detecting cancer at a less advanced stage.

NCI is funding a large-scale randomized breast screening trial, the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) , to compare the number of advanced cancers detected in women screened for 5 years with 3-D mammography with the number detected in women screened with 2-D mammography. 

Two concerns in breast cancer screening, as in all cancer screening, are:

• the potential for diagnosing tumors that would not have become life-threatening ( overdiagnosis )
• the possibility of receiving false-positive test results, and the anxiety that comes with follow-up tests or procedures

As cancer treatment is becoming more individualized, researchers are looking at ways to personalize breast cancer screening. They are studying screening methods that are appropriate for each woman’s level of risk and limit the possibility of overdiagnosis.

For example, the Women Informed to Screen Depending on Measures of Risk (WISDOM) study aims to determine if risk-based screening—that is, screening at intervals that are based on each woman’s risk as determined by her genetic makeup, family history , and other risk factors—is as safe, effective, and accepted as standard annual screening mammography.

WISDOM is also making a focused effort to enroll Black women in the trial. Past studies  tended to contain a majority of White women and therefore, there is less data on how screening can benefit Black women. Researchers are taking a number of steps to include as many Black women as possible in the study while also increasing the diversity of all women enrolled.

Breast Cancer Treatment

The mainstays of breast cancer treatment are surgery , radiation , chemotherapy , hormone therapy , and targeted therapy . But scientists continue to study novel treatments and drugs, along with new combinations of existing treatments.

It is now known that breast cancer can be divided into subtypes based on whether they:

• are hormone receptor (HR) positive which means they express  estrogen and/or progesterone receptors  ( ER , PR )

Shortening Radiation Therapy for Some with Early Breast Cancer

A condensed course was as effective and safe as the standard course for women with higher-risk early-stage breast cancer who had a lumpectomy.

As we learn more about the subtypes of breast cancer and their behavior, we can use this information to guide treatment decisions. For example:

• The NCI-sponsored TAILORx clinical trial. The study, which included patients with ER-positive, lymph node-negative breast cancer, found that a test that looks at the expression of certain genes can predict which women can safely avoid chemotherapy.
• The RxPONDER trial found that the same gene expression test can also be used to determine treatment options in women with more advanced breast cancer. The study found that some postmenopausal women with HR positive, HER-2 negative breast cancer that has spread to several lymph nodes and has a low risk of recurrence do not benefit from chemotherapy when added to their hormone therapy. 
• The OFSET trial is comparing the addition of chemotherapy to usual treatment ( ovarian function suppression plus hormone therapy) to usual treatment alone in treating premenopausal estrogen receptor (ER)-positive/HER2-negative breast cancer patients who are at high risk of their cancer returning. This will help determine whether or not adding chemotherapy helps prevent the cancer from returning.  

Genomic analyses, such as those carried out through  The Cancer Genome Atlas (TCGA) , have provided more insights into the molecular diversity of breast cancer and eventually could help identify even more breast cancer subtypes. That knowledge, in turn, may lead to the development of therapies that target the genetic alterations that drive those cancer subtypes.

HR-Positive Breast Cancer Treatment 

Hormone therapies have been a mainstay of treatment for HR-positive cancer. However, there is a new focus on adding targeted therapies to hormone therapy for advanced or metastatic HR-positive cancers. These treatments could prolong the time until chemotherapy is needed and ideally, extend survival. Approved drugs include:

Drug Combo Effective for Metastatic Breast Cancer in Younger Women

Ribociclib plus hormone therapy were superior to standard chemotherapy combos in a recent trial.

• Palbociclib (Ibrance) ,  ribociclib (Kisqali) , and  everolimus (Afinitor) have all been approved by the FDA for use with hormone therapy for treatment of advanced or metastatic breast cancer. Ribociclib has been shown to increase the survival of patients with metastatic breast cancer . It has also shown to slow the growth of metastatic cancer in younger women when combined with hormone therapy.
• Elacestrant (Orserdu) is approved for HR-positive and HER2-negative breast cancer that has a mutation in the ESR1 gene, and has spread. It is used in postmenopausal women and in men whose cancer has gotten worse after at least one type of hormone therapy.
• Abemaciclib (Verzenio) can be used with or after hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancer. In October 2021, the Food and Drug Administration ( FDA ) approved abemaciclib in combination with hormone therapy to treat some people who have had surgery for early-stage HR-positive, HER2-negative breast cancer.
• Alpelisib (Piqray)  is approved to be used in combination with hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancers that have a mutation in the PIK3CA gene .
• Sacituzumab govitecan-hziy (Trodelvy) is used for HR-positive and HER2-negative breast cancer that has spread or can't be removed with surgery. It is used in those who have received hormone therapy and at least two previous treatments. It has shown to extend the amount of time that the disease doesn't get worse ( progression-free survival ) and also shown to improve overall survival .

HER2-Positive Breast Cancer Treatment 

The FDA has approved a number of targeted therapies to treat HER2-positive breast cancer , including:

• Trastuzumab (Herceptin) has been approved to be used to prevent a relapse in patients with early-stage HER2-positive breast cancer. 
• Pertuzumab (Perjeta) is used to treat metastatic HER2-positive breast cancer, and also both before surgery ( neoadjuvant ) and after surgery ( adjuvant therapy ). 
• Trastuzumab and pertuzumab together can be used in combination with chemotherapy to prevent relapse in people with early-stage HER2-positive breast cancer.  Both are also used together in metastatic disease, where they delay progression and improve overall survival. 
• Trastuzumab deruxtecan (Enhertu) is approved for patients with advanced or metastatic HER2-positive breast cancer who have previously received a HER2-targeted treatment. A 2021 clinical trial showed that the drug lengthened the time that people with metastatic HER2-positive breast cancer lived without their cancer progressing. The trial also showed that it was better at shrinking tumors than another targeted drug, trastuzumab emtansine (Kadcyla).
• Tucatinib (Tukysa) is approved to be used in combination with trastuzumab and capecitabine (Xeloda) for HER2-positive breast cancer that cannot be removed with surgery or is metastatic. Tucatinib is able to cross the blood–brain barrier, which makes it especially useful for HER2-positive metastatic breast cancer, which tends to spread to the brain. 
• Lapatinib (Tykerb)  has been approved for treatment of some patients with HER2-positive advanced or metastatic breast cancer, together with capecitabine or letrozole.
• Neratinib Maleate (Nerlynx) can be used in patients with early-stage HER2-positive breast cancer and can also be used together with capecitabine (Xeloda) in some patients with advanced or metastatic disease.
• Ado-trastuzumab emtansine (Kadcyla) is approved to treat patients with metastatic HER2-positive breast cancer who have previously received trastuzumab and a taxane . It's also used in some patients with early-stage HER2-positive breast cancer who have completed therapy before surgery ( neoadjuvant ) and have residual disease at the time of surgery.

HER2-Low Breast Cancer

 A newly defined subtype, HER2-low, accounts for more than half of all metastatic breast cancers. HER2-low tumors are defined as those whose cells contain lower levels of the HER2 protein on their surface. Such tumors have traditionally been classified as HER2-negative because they did not respond to drugs that target HER2. 

However, in a clinical trial, trastuzumab deruxtecan (Enhertu) improved the survival of patients with HER2-low breast cancer compared with chemotherapy , and the drug is approved for use in such patients. 

Immunotherapy Improves Survival in Triple-Negative Breast Cancer

For patients whose tumors had high PD-L1 levels, pembrolizumab with chemo helped them live longer.

Triple-Negative Breast Cancer Treatment 

Triple-negative breast cancers (TNBC) are the hardest to treat because they lack both hormone receptors and HER2 overexpression , so they do not respond to therapies directed at these targets. Therefore, chemotherapy is the mainstay for treatment of TNBC. However, new treatments are starting to become available. These include:

• Sacituzumab govitecan-hziy (Trodelvy)  is approved to treat patients with TNBC that has spread to other parts of the body . Patients must have received at least two prior therapies before receiving the drug.
• Pembrolizumab (Keytruda)  is an immunotherapy drug that is approved to be used in combination with chemotherapy for patients with locally advanced or metastatic TNBC that has the PD-L1 protein. It may also be used before surgery (called neoadjuvant ) for patients with early-stage TNBC, regardless of their PD-L1 status.
• PARP inhibitors, which include olaparib (Lynparza) and talazoparib (Talzenna) , are approved to treat metastatic HER2-negative or triple-negative breast cancers in patients who have inherited a harmful BRCA gene mutation. Olaparib is also approved for use in certain patients with early-stage HER2-negative or triple-negative breast cancer. 
• Drugs that block the androgen receptors  or prevent androgen production are being tested in a subset of TNBC that express the androgen receptor.

For a complete list of drugs for breast cancer, see Drugs Approved for Breast Cancer .

NCI-Supported Breast Cancer Research Programs

Many NCI-funded researchers working at the NIH campus, as well as across the United States and world, are seeking ways to address breast cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some are more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in breast cancer.

TMIST is a randomized breast screening trial that compares two Food and Drug Administration (FDA)-approved types of digital mammography, standard digital mammography (2-D) with a newer technology called tomosynthesis mammography (3-D).

The  Breast Specialized Programs of Research Excellence (Breast SPOREs)  are designed to quickly move basic scientific findings into clinical settings. The Breast SPOREs support the development of new therapies and technologies, and studies to better understand tumor resistance, diagnosis, prognosis, screening, prevention, and treatment of breast cancer.

The NCI Cancer Intervention and Surveillance Modeling Network (CISNET) focuses on using modeling to improve our understanding of how prevention, early detection, screening, and treatment affect breast cancer outcomes.

The Confluence Project , from NCI's Division of Cancer Epidemiology and Genetics (DCEG) , is developing a research resource that includes data from thousands of breast cancer patients and controls of different races and ethnicities. This resource will be used to identify genes that are associated with breast cancer risk, prognosis, subtypes, response to treatment, and second breast cancers. (DCEG conducts other breast cancer research as well.)

The Black Women’s Health Study (BWHS) Breast Cancer Risk Calculator allows health professionals to estimate a woman’s risk of developing invasive breast cancer over the next 5 years. With the NCI-funded effort, researchers developed a tool to estimate the risk of breast cancer in US Black women. The team that developed the tool hopes it will help guide more personalized decisions on when Black women—especially younger women—should begin breast cancer screening. 

The goal of the Breast Cancer Surveillance Consortium (BCSC) , an NCI-funded program launched in 1994, is to enhance the understanding of breast cancer screening practices in the United States and their impact on the breast cancer's stage at diagnosis, survival rates, and mortality.

There are ongoing programs at NCI that support prevention and early detection research in different cancers, including breast cancer. Examples include:

• The  Cancer Biomarkers Research Group , which promotes research in cancer biomarkers and manages the Early Detection Research Network (EDRN) . EDRN is a network of NCI-funded institutions that are collaborating to discover and validate early detection biomarkers. Within the EDRN, the Breast and Gynecologic Cancers Collaborative Group conducts research on breast and ovarian cancers.
• NCI's Division of Cancer Prevention  houses the Breast and Gynecologic Cancer Research Group which conducts and fosters the development of research on the prevention and early detection of  breast and gynecologic cancers.

Breast Cancer Survivorship Research

NCI’s Office of Cancer Survivorship, part of the Division of Cancer Control and Population Sciences (DCCPS), supports research projects throughout the country that study many issues related to breast cancer survivorship. Examples of studies funded include the impact of cancer and its treatment on physical functioning, emotional well-being, cognitive impairment , sleep disturbances, and cardiovascular health. Other studies focus on financial impacts, the effects on caregivers, models of care for survivors, and issues such as racial disparities and communication.

Breast Cancer Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for breast cancer prevention , screening , and treatment . 

Breast Cancer Research Results

The following are some of our latest news articles on breast cancer research and study updates:

• How Breast Cancer Risk Assessment Tools Work
• Can Some People with Breast Cancer Safely Skip Lymph Node Radiation?
• Study Adds to Debate about Mammography in Older Women
• Pausing Long-Term Breast Cancer Therapy to Become Pregnant Appears to Be Safe
• A Safer, Better Treatment Option for Some Younger Women with Breast Cancer
• Shorter Course of Radiation Is Effective, Safe for Some with Early-Stage Breast Cancer

View the full list of Breast Cancer Research Results and Study Updates .

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Breast cancer

• Breast cancer caused 670 000 deaths globally in 2022.
• Roughly half of all breast cancers occur in women with no specific risk factors other than sex and age.
• Breast cancer was the most common cancer in women in 157 countries out of 185 in 2022.
• Breast cancer occurs in every country in the world.
• Approximately 0.5–1% of breast cancers occur in men.

Breast cancer is a disease in which abnormal breast cells grow out of control and form tumours. If left unchecked, the tumours can spread throughout the body and become fatal.

Breast cancer cells begin inside the milk ducts and/or the milk-producing lobules of the breast. The earliest form (in situ) is not life-threatening and can be detected in early stages. Cancer cells can spread into nearby breast tissue (invasion). This creates tumours that cause lumps or thickening. 

Invasive cancers can spread to nearby lymph nodes or other organs (metastasize). Metastasis can be life-threatening and fatal.

Treatment is based on the person, the type of cancer and its spread. Treatment combines surgery, radiation therapy and medications.

Scope of the problem

In 2022, there were 2.3 million women diagnosed with breast cancer and 670 000 deaths globally. Breast cancer occurs in every country of the world in women at any age after puberty but with increasing rates in later life.   Global estimates reveal striking inequities in the breast cancer burden according to human development. For instance, in countries with a very high Human Development Index (HDI), 1 in 12 women will be diagnosed with breast cancer in their lifetime and 1 in 71 women die of it.

In contrast, in countries with a low HDI; while only 1 in 27 women is diagnosed with breast cancer in their lifetime, 1 in 48 women will die from it.

Who is at risk?

Female gender is the strongest breast cancer risk factor. Approximately 99% of breast cancers occur in women and 0.5–1% of breast cancers occur in men. The treatment of breast cancer in men follows the same principles of management as for women.

Certain factors increase the risk of breast cancer including increasing age, obesity, harmful use of alcohol, family history of breast cancer, history of radiation exposure, reproductive history (such as age that menstrual periods began and age at first pregnancy), tobacco use and postmenopausal hormone therapy. Approximately half of breast cancers develop in women who have no identifiable breast cancer risk factor other than gender (female) and age (over 40 years). 

Family history of breast cancer increases the risk of breast cancer, but most women diagnosed with breast cancer do not have a known family history of the disease. Lack of a known family history does not necessarily mean that a woman is at reduced risk.

Certain inherited high penetrance gene mutations greatly increase breast cancer risk, the most dominant being mutations in the genes BRCA1, BRCA2 and PALB-2. Women found to have mutations in these major genes may consider risk reduction strategies such as surgical removal of both breasts or chemoprevention strategies. 

Signs and symptoms

Most people will not experience any symptoms when the cancer is still early hence the importance of early detection.

Breast cancer can have combinations of symptoms, especially when it is more advanced. Symptoms of breast cancer can include:

• a breast lump or thickening, often without pain 
• change in size, shape or appearance of the breast
• dimpling, redness, pitting or other changes in the skin
• change in nipple appearance or the skin surrounding the nipple (areola) 
• abnormal or bloody fluid from the nipple.

People with an abnormal breast lump should seek medical care, even if the lump does not hurt. 

Most breast lumps are not cancer. Breast lumps that are cancerous are more likely to be successfully treated when they are small and have not spread to nearby lymph nodes. 

Breast cancers may spread to other areas of the body and trigger other symptoms. Often, the most common first detectable site of spread is to the lymph nodes under the arm although it is possible to have cancer-bearing lymph nodes that cannot be felt. 

Over time, cancerous cells may spread to other organs including the lungs, liver, brain and bones. Once they reach these sites, new cancer-related symptoms such as bone pain or headaches may appear. 

Treatment for breast cancer depends on the subtype of cancer and how much it has spread outside of the breast to lymph nodes (stages II or III) or to other parts of the body (stage IV).

Doctors combine treatments to minimize the chances of the cancer coming back (recurrence). These include:

• surgery to remove the breast tumour
• radiation therapy to reduce recurrence risk in the breast and surrounding tissues
• medications to kill cancer cells and prevent spread, including hormonal therapies, chemotherapy or targeted biological therapies.

Treatments for breast cancer are more effective and are better tolerated when started early and taken to completion. 

Surgery may remove just the cancerous tissue (called a lumpectomy) or the whole breast (mastectomy). Surgery may also remove lymph nodes to assess the cancer’s ability to spread.

Radiation therapy treats residual microscopic cancers left behind in the breast tissue and/or lymph nodes and minimizes the chances of cancer recurring on the chest wall.

Advanced cancers can erode through the skin to cause open sores (ulceration) but are not necessarily painful. Women with breast wounds that do not heal should seek medical care to have a biopsy performed.

Medicines to treat breast cancers are selected based on the biological properties of the cancer as determined by special tests (tumour marker determination).  The great majority of drugs used for breast cancer are already on the WHO Essential Medicines List (EML).

Lymph nodes are removed at the time of cancer surgery for invasive cancers. Complete removal of the lymph node bed under the arm (complete axillary dissection) in the past was thought to be necessary to prevent the spread of cancer. A smaller lymph node procedure called “sentinel node biopsy” is now preferred as it has fewer complications. 

Medical treatments for breast cancers, which may be given before (“neoadjuvant”) or after (“adjuvant”) surgery, is based on the biological subtyping of the cancers. Certain subtypes of breast cancer are more aggressive than others such as triple negative (those that do not express estrogen receptor (ER), progesterone receptor (PR) or HER-2 receptor). Cancer that express the estrogen receptor (ER) and/or progesterone receptor (PR) are likely to respond to endocrine (hormone) therapies such as tamoxifen or aromatase inhibitors.  These medicines are taken orally for 5–10 years and reduce the chance of recurrence of these “hormone-positive” cancers by nearly half. Endocrine therapies can cause symptoms of menopause but are generally well tolerated.

Cancers that do not express ER or PR are “hormone receptor negative” and need to be treated with chemotherapy unless the cancer is very small. The chemotherapy regimens available today are very effective in reducing the chances of cancer spread or recurrence and are generally given as outpatient therapy. Chemotherapy for breast cancer generally does not require hospital admission in the absence of complications.

Breast cancers that independently overexpress a molecule called the HER-2/neu oncogene (HER-2 positive) are amenable to treatment with targeted biological agents such as trastuzumab. When targeted biological therapies are given, they are combined with chemotherapy to make them effective at killing cancer cells.

Radiotherapy plays a very important role in treating breast cancer. With early-stage breast cancers, radiation can prevent a woman having to undergo a mastectomy. With later stage cancers, radiotherapy can reduce cancer recurrence risk even when a mastectomy has been performed. For advanced stages of breast cancer, in some circumstances, radiation therapy may reduce the likelihood of dying of the disease.

The effectiveness of breast cancer therapies depends on the full course of treatment. Partial treatment is less likely to lead to a positive outcome. 

Global impact

Age-standardized breast cancer mortality in high-income countries dropped by 40% between the 1980s and 2020 (1) . Countries that have succeeded in reducing breast cancer mortality have been able to achieve an annual breast cancer mortality reduction of 2–4% per year. 

The strategies for improving breast cancer outcomes depend on fundamental health system strengthening to deliver the treatments that are already known to work. These are also important for the management of other cancers and other non-malignant noncommunicable diseases (NCDs). For example, having reliable referral pathways from primary care facilities to district hospitals to dedicated cancer centres.

The establishment of reliable referral pathways from primary care facilities to secondary hospitals to dedicated cancer centres is the same approach as is required for the management of cervical cancer, lung cancer, colorectal cancer and prostate cancer. To that end, breast cancer is a so-called index disease whereby pathways are created that can be followed for the management of other cancers. 

WHO response

The objective of the WHO Global Breast Cancer Initiative (GBCI) is to reduce global breast cancer mortality by 2.5% per year, thereby averting 2.5 million breast cancer deaths globally between 2020 and 2040. Reducing global breast cancer mortality by 2.5% per year would avert 25% of breast cancer deaths by 2030 and 40% by 2040 among women under 70 years of age. The three pillars toward achieving these objectives are: health promotion for early detection; timely diagnosis; and comprehensive breast cancer management.  

By providing public health education to improve awareness among women of the signs and symptoms of breast cancer and, together with their families, understand the importance of early detection and treatment, more women would consult medical practitioners when breast cancer is first suspected, and before any cancer present is advanced. This is possible even in the absence of mammographic screening that is impractical in many countries at the present time.

• Age-standardization is a technique used to allow populations to be compared when the age profiles of the populations are quite different.

Global Breast Cancer Initiative

More on cancer

Editor's Choice: JAMA Oncology —The Year in Review, 2023

Mahmoud Yousef, MD, MS; Abdelrahman Yousef, MD; Saikat Chowdhury, PhD; et al

Original Investigation | September 12, 2024

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ESMO: With survival win, Merck's Keytruda redeems itself in early triple-negative breast cancer

In 2021, the FDA blasted Merck for using a premature endpoint to pursue a Keytruda approval in early-stage triple-negative breast cancer (TNBC). Now, the PD-1 inhibitor has gold-standard overall survival data to back its case.

Keytruda plus neoadjuvant chemotherapy before surgery, followed by Keytruda after surgery, reduced the risk of death by 34% compared with presurgical chemo alone in patients with high-risk nonmetastatic TNBC. The statistically significant result came from the KEYNOTE-522 trial after a median follow-up of more than six years.

At a prespecified data cut-off in March 2024, 14.7% of patients in the Keytruda arm had passed away, versus 21.8% in the control arm. Investigators estimated that the five-year overall survival rate was 86.6% versus 81.7%, respectively, between the two groups. The results will be presented at the European Society for Medical Oncology 2024 annual meeting.

The overall survival findings bolster Keytruda’s case as a perioperative therapy in early-stage TNBC following an FDA approval in 2021. For that approval, the agency considered event-free survival (EFS) data showing the therapy reduced the risk of disease recurrence, progression, development of new cancer or death by 37% over solo chemotherapy used only in the presurgery, neoadjuvant phase.

The 2021 approval came a few months after the FDA rejected Merck’s original bid to use pathological complete response (pCR)—which was defined as absence of invasive cancer in the breast and lymph nodes at the time of surgery—and immature EFS data in its application. EFS and pCR are the KEYNOTE-522 trial’s dual primary endpoints, and overall survival is a key secondary endpoint.

In the current analysis, Keytruda’s EFS benefit remained strong, with the drug showing a 35% improvement over neoadjuvant chemo alone. The five-year EFS rate was 81.2% for Keytruda and 72.2% for control.

“We had thought that breast cancer may not be sensitive to immunotherapy alone but giving it in combination with chemotherapy before surgery and then further afterwards improves overall survival in many patients,” Alessandra Curioni-Fontecedro, M.D., director of oncology at the Hospital of Fribourg in Switzerland, said in an ESMO-facilitated statement. “The finding suggests the possibility that the combination of treatments might lead to a sensitization of TNBC to immunotherapy.”

Keytruda’s KEYNOTE-522 win sets it apart from Roche’s PD-L1 inhibitor Tecentriq. Last year, following an interim analysis, Roche discontinued the phase 3 IMpassion030 trial, which was testing Tecentriq in combination with chemo as a postsurgical adjuvant therapy in TNBC. Data later revealed that the risk of recurrence or death appeared to be even higher for Tecentriq-chemo versus adjuvant chemo alone.

Then there’s the IMpassion031 trial, which, like KEYNOTE-522, evaluated Tecentriq alongside chemo before surgery followed by Tecentriq after surgery in early-stage TNBC. Although neoadjuvant Tecentriq showed a significant pCR benefit, the entire regimen only numerically improved EFS, as a 24% reduction in the risk of recurrence or death failed to cross the statistical significance bar. 

After around 40 months of median follow-up from randomization, overall survival also favored Tecentriq with a 44% reduction in the risk of death, which again wasn’t statistically significant.

Merck is now trying to further improve upon the KEYNOTE-522 regimen with its Kelun Biotech-partnered antibody-drug conjugate sacituzumab tirumotecan (sac-TMT). In the phase 3 TroFuse-012 trial, the combination of Keytruda and the TROP2-directed ADC is being pitted against Keytruda with or without chemo in TNBC patients who didn’t achieve a pCR at surgery following neoadjuvant treatment based on the KEYNOTE-522 regimen.

Merck kicked off the study in June with the goal to enroll 1,530 patients. With invasive disease-free survival as the primary endpoint, the trial currently bears an estimated primary completion date in late 2030.

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BRCA1 and Breast Cancer: Molecular Mechanisms and Therapeutic Strategies

1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China

2 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China

3 Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Huadong Pei

4 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States

Juanjuan Li

Jiadong Wang , Peking University Health Science Centre, China

Associated Data

Breast cancer susceptibility gene 1 ( BRCA1 ) is a tumor suppressor gene, which is mainly involved in the repair of DNA damage, cell cycle regulation, maintenance of genome stability, and other important physiological processes. Mutations or defects in the BRCA1 gene significantly increase the risk of breast, ovarian, prostate, and other cancers in carriers. In this review, we summarized the molecular functions and regulation of BRCA1 and discussed recent insights into the detection and treatment of BRCA1 mutated breast cancer.

Introduction

Breast cancer (BC) is the most common malignancy all over the world, accounting for 11.7% of new cancer cases ( Sung et al., 2021 ). Up to 7% of unselected BC patients have a definite germline genetic mutation called hereditary breast cancer (HBC) ( Claus et al., 1996 ). Among them, breast cancer susceptibility gene 1 ( BRCA1 ) is one of the most common tumor suppressor genes, which encodes a 220 kD nuclear protein and is detected in at least 5% of unselected patients with BC ( Hall et al., 1990 ; Chen et al., 1996 ). BRCA1 plays an important role in DNA repair, replication fork protection, cell cycle regulation, and gene transcription regulation ( Gudmundsdottir and Ashworth, 2006 ). When the BRCA1 gene is mutated or lost, the incidence of BC and ovarian cancer will increase significantly ( Miki, et al., 1994 ). The cumulative risk of BC by 80 years of age in healthy female carriers of BRCA1 mutation is about 80% ( Kuchenbaecker et al., 2017 ; King et al., 2003 ) while one in eight women will develop BC over the lifespan in the general population. Carriers of BRCA1 mutation are more likely to develop triple-negative breast cancer (TNBC), which suggests that BRCA1 mutation and the hormone receptor status are interlinked ( Foulkes et al., 2004 ). BRCA1 -mutated BC is associated with earlier onset, more aggressive disease, and a higher risk of relapse. Hence, it is important to investigate the function and dysregulation of BRCA1 in BC and treatment strategies for this population. In this article, we provide a comprehensive overview of BRCA1 in BC, including the BRCA1’s molecular function, its mutation detection, and the prevention and treatment of BC in mutated carriers.

Structure and Function of BRCA1 Gene

BRCA1 is an incomplete recessive gene on an autosome, located on chromosome 17q21 and encoded 220 kD protein-containing multi-function domains ( Hall et al., 1990 ). There are 24 exons in BRCA1 whose exons 2–5 encode the RING domain and exons 15–23 encode the BRCA1 C-terminal (BRCT) domain ( Figure 1 ) ( Miki et al., 1994 ; Clark et al., 2012 ). The N-terminal RING domain has an E3 ligase activity, which interacts with its partner protein, the BRCA1 -associated RING domain protein 1 (BARD1) to form a stable BRCA1-BARD1 heterodimer ( Hashizume et al., 2001 ). The BRCT domain is associated with different phosphorylated interacting proteins. In addition to the N-terminal RING domain and C-terminal domain, there is a coiled-coil domain upstream of BRCT domains, which binds another coiled-coil domain at the N-terminus of PALB2. PALB2 also binds BRCA2 and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex ( Shirley et al., 2009 ; Zhang et al., 2009 ). In mammalian cells, homologous recombination (HR) and non-homologous end-joining (NHEJ) are two major repair pathways to repair DNA double-strand breaks (DSBs) for genome integrity. Both the RING domain and BRCT domain of BRCA1 are essential for HR to maintain genome stability. Many clinically important mutations of BRCA1 gene frequently target these two domains.

The domain structure of BRCA1. The RING domain in blue, the two NLS domain in red, the coiled coil domain in orange, and the two BRCT domains in green. BRCA1 can form four different complexes: BRCA1/RAP80/Abraxas complex, BRCA1/BACH1 complex, BRCA1/PALB2/BRCA2 complex and BRCA1/CtIP complex.

The BRCT domain is conserved in several DNA damage response (DDR) proteins and is responsible for BRCA1 to recognize a phospho-SPxF motif (S, serine; P, proline; x, varies; F, phenylalanine) ( Wang, 2012 ; Chabanon et al., 2021 ). Figure 2 BRCA1 can form four different complexes in cells, through the association of different adaptor proteins with the BRCT domain, such as BRCA1/RAP80/Abraxas complex, BRCA1/BACH1( BRCA1 associated C-terminal helicase) complex, BRCA1/PALB2 (partner and localizer of BRCA2 ) / BRCA2 complex, and BRCA1/CtIP complex ( Figure 1 ). BRCA1/RAP80/Abraxas complex is recruited to DNA DSBs through RAP80, a ubiquitin-binding protein. RAP80 could target this complex to MDC1-rH2AX-dependent K6 and K63-linked ubiquitin polymers at DSBs. BRCA1/RAP80/Abraxas complex prevents excessive end resection and potentially deleterious homology-directed DSB repair mechanisms ( Huang and Zhou, 2020 ; Vohhodina et al., 2020 ). The helicase catalytic function of BRCA1/BACH1 is not only important for BRCA1-mediated DDR but also necessarily required to maintain DNA damage-induced G2/M checkpoint ( Yu et al., 2003 ). As described previously, PALB2, the partner and localizer of BRCA2, could bind directly to BRCA1 to form BRCA1/PALB2/BRCA2 complex, which stimulates RAD51-mediated localization and repair at DNA breaks ( Shirley et al., 2009 ; Ducy et al., 2019 ). Lastly, BRCA1/CtIP complex promotes the HR by DNA end resection.

Types of DNA damage. DNA single-strand breaks: BER (base excision repair); bulky adducts: NER (nucleotide excision repair); base mismatches, insertions and deletions: MMR (Mismatch repair); R-loops caused double strand breaks (DSB): NHEJ (Non-homologous end joining) and HRR (homologous recombination repair); DNA double-strand breaks: NHEJ and HRR; G-quadruplex caused DSB: NHEJ, and HRR.

In addition to its critical roles in DSB repair, BRCA1 is also involved in the repair and restart of stalled and damaged DNA replication forks and in the protection from nucleolytic attack and degradation. BRCA1-mediated fork protection functions independently from its role in the HR-mediated repair of DNA DSBs ( Schlacher et al., 2012 ; Long et al., 2014 ). Upon replication fork stress, BRCA1 protects nascent DNA strands from degradation by stabilizing RAD51 nucleofilaments that affect the exonuclease activity of MRE11 ( Schlacher et al., 2012 ). RAD51 is also required for fork restart once halted forks are repaired in response to short replication blocks ( Petermann et al., 2010 ). Moreover, BRCA1 also has important roles in gene transcription. Gerald M. Pao et al . have shown that the carboxyl terminus of BRCA1 transactivates the heterologous promoters ( Pao et al., 2000 ). This BRCA1-mediated transactivation could be mediated by RNA polymerase II (Pol II) via RNA helicase A (RHA) and enhanced by transcriptional coactivators/acetyltransferases p300 and CBP (p300/CBP). Zhu et al. also showed that BRCA1 could bind to satellite DNA regions and ubiquitylates the histone H2A to maintain the heterochromatin structures ( Zhu et al., 2011 ; Zhu et al., 2018 ); Bochar et al. ( Bochar et al., 2000 ) reported that BRCA1 is a component of SWI/SNF chromatin remodeling complex and controls the transcription through the modulation of chromatin structure. RNA/DNA hybrid structures (R-loops) as normal transcriptional intermediates also affect transcription and genomic instability. BRCA1 is recruited to transcriptional pause sites and mediates the recruitment of senataxin (SETX) ( Hatchi et al., 2015 ); SETX is involved in processing replication forks and resolves R-loops at transcriptional sites; thus, BRCA1/SETX addresses R-loop associated DNA damage arising at transcriptional pause sites. Recently, other studies showed that BRCA1 aberrantly retains at the transcription regions with increasing R-loop levels and decreases its distribution at DNA damage regions in Ewing sarcoma cells ( Gorthi et al., 2018 ). As a result, these cells could not inhibit the transcription after DNA damage and showed a defect in HR repair. Furthermore, Steffi Herold et al. found more details about the relationship between BRCA1, R-loop, and transcriptional regulation in human neuroblastoma cells ( Herold et al., 2019 ). In the MYCN-amplified cells, MYCN activation could increase the transcriptional elongation by inducing the escape of RNAPII from promoters. The recruitment of BRCA1 to the promoter-proximal regions could stabilize MYCN on the chromatin and prevent R-loop formation caused by the RNAPII stalling at the transcription-suspended sites.

The Mutation of BRCA1 and Breast Cancer

Since the first clone of the BRCA1 gene in 1994 ( Miki et al., 1994 ), variable cut transcripts were found as a “naturally occurring” event in both tumor and normal tissues by many studies ( Li et al., 2019 ). There are at least six alternative splicing transcripts of BRCA1 discovered, including BRCA1 exon 1a, exon 1b, exon 1c, BRCA1 a (∆11q, ∆11), BRCA1 b (∆9,10), and BRCA1-IRIS , which codes protein products with different molecular weights. Based on these observations, Walker et al. revised 77 published studies with 252 BRCA1 splicing analysis assays and found that some of the exon boundary variants may not perform as a loss of function, leading to a naturally occurring in-frame RNA isoform ( Walker et al., 2013 ). Compared to the complete transcript of BRCA1 , the variable-cut transcripts of BRCA1 can have similar or opposite functions and, in some cases, may have more unique functions ( Braunschweig et al., 2013 ). Up to now, 1,800 mutations have been found in human BRCA1 , including intron mutations, missense mutations, nonsense mutations, frameshift mutations, and other types. These mutations often occur in the RING and BRCT domains, which are the key domains in BRCA1 for genome integrity ( Supplementary Data Sheet ). Missense mutations in BRCA1 present a significant challenge for the prevention and treatment of patients. For example, BRCA1 c.5309G > T p. (Gly1770Val) has been shown to inhibit homologous recombination and could be considered as a disease-causing mutation ( Tudini et al., 2018 ). As a benefit from bioinformatic analysis, more variants of BRCA1 can be found from public databases, such as the cBioPortal database ( http://www.cbioportal.org/ ), ENIGMA ( https://enigmaconsortium.org/ ), BRCA Exchange ( https://brcaexchange.org ), and ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar/ ).

Patients with BRCA1 mutations have a higher risk for cancer. The estimated lifetime risk of BC is about 80%, and the lifetime risk of ovarian cancer is 40%–65% ( King et al., 2003 ; Kuchenbaecker et al., 2017 ), which might alter according to the type and location of the mutations ( Rebbeck, et al., 2015 ). BRCA1 gene deletion with or without p53 defect leads to a high incidence of basal-like BC and tends to form TNBC, which is the most aggressive type of BC ( Tarsounas and Sung, 2020 ). Some studies show that the TNBC in BRCA1 mutation carriers originated from luminal progenitor cells, not basal stem cells ( Lim et al., 2009 ; Molyneux et al., 2010 ). If BRCA1/p53 is perturbed in luminal progenitors, it could induce the abnormal alveolar differentiation premalignancy with pro-tumorigenic changes in the immune compartment. It belongs to cell autonomy and is caused by the dysregulation of transcription factors. This study explains how BRCA1 aberration impacts the state of nascent tumor cells and their microenvironment. Bach et al. found that breast cells with BRCA1 mutations undergo changes similar to those common changes in women during pregnancy ( Bach et al., 2021 ). Based on the data, they proposed a model in which BRCA1/p53 -driven transcriptional and epigenetic changes inadvertently promote innate differentiation programs in luminal progenitors accompanied by protumorigenic changes in the immune compartment, highlighting the decisive role of the origin cell and providing a potential explanation for the tissue specificity of BRCA1 tumors. Researchers have mapped early changes in seemingly healthy breast tissue before tumors appear, which may have great significance for the early diagnosis of BC ( Bach et al., 2021 ).

In addition to familial BC, BRCA1 gene silencing due to promoter methylation can also lead to sporadic BC ( Esteller et al., 2000 ). A study of tumor xenografts from TNBC patients ( Ter Brugge et al., 2016 ) revealed a novel resistance mechanism in BRCA1 -methylated PDX (patient-derived xenograft) tumors. Next-generation sequencing (NGS) data showed that the genome rearrangement places the BRCA1 gene under the transcriptional control of the heterologous promoter, which results in the re-expression of BRCA1 in a subset of BRCA1 -mutated PDX tumors and leads to acquired resistance to PARP [poly (ADP-ribose) polymerase 1,2] inhibitor (PARPi) and cisplatin chemotherapy ( Ter Brugge et al., 2016 ). This is a unique example of genomic plasticity that is caused by the treatment of BRCA1 -deficient tumors, but it can lead to tumor regeneration.

Detection of BRCA1 Gene Mutations

The BRCA1 genetic test is designed to identify harmful changes in BRCA1 using a blood test. People who inherit mutation in BRCA1 gene are at an increased risk of developing BC and ovarian cancer than the general population. Therefore, the BRCA1 gene test has been widely used by physicians to develop risk-reducing strategies for those who are likely to have an inherited mutation based on personal or family history. Additionally, BRCA1 mutation is a prognostic and predictive biomarker for BC. Although studies provided conflicting interpretations of the prognostic value of BRCA1 mutation in BC patients ( Lee et al., 2010 ; Copson et al., 2018 ), patients with BRCA1 mutation may be sensitive to platinum salts and PARP inhibitors, which could significantly prolong survival time. Hence, BRCA1 genetic testing is essential for making individualized therapy for selected BC patients. According to the consensus of experts and guidelines, the criteria for candidates to do BRCA1 genetic testing are ( Daly et al., 2021 ): 1) BC patients before the age of 40 years; 2) BC patients before the age of 50 years old who had a second primary BC or a history of BC or pancreatic or prostate cancer in their relatives; 3) patients with TNBC before the age of 60 years old; 4) all male BC patients; 5) patients with bilateral BC; and 6) Patients with a relevant family history at any age, who want to be assessed for cancer risk.

The common gene detection methods for BRCA1 mutations include Sanger sequencing, NGS, multiplex ligation-dependent probe amplification (MLPA), massively parallel signature sequencing (MPSS), chromosomal microarray (CMA), and array comparative genomic hybridization (aCGH). ( Toland et al., 2018 ). So far, no single technique can detect all mutations in the BRCA1 gene ( Walsh et al., 2010 ).

In order to reduce the rate of missed detection, a combination of several methods is used to detect all mutations. Previously, BRCA1 gene detection is mainly performed by Sanger sequencing and MLPA, which can screen out single-nucleotide mutation, small fragment mutation, and large copy number mutation (CNVs). Nowadays, NGS is generally used for gene detection as a high-throughput gene sequencing technology ( Plagnol et al., 2012 ). After the genomic DNA has been cut into small fragments, the end of the molecule is connected to the sequencing preparation library and the sequencing results are obtained after image collection and analysis ( Gao and Smith, 2020 ). Compared with the previous gold standard Sanger sequencing, NGS is both cost and time effective, high throughput with simple operation, and operatable in clinical practice. The disadvantage is the increased error rate by introducing polymerase chain reaction in sequencing ( Suryavanshi et al., 2017 ). For the detection of BRCA1 gene mutations in the real world, there are two major patterns. It is recommended to use NGS technology combined with large fragment deletion detection to detect all exons of BRCA gene and the junction region between exons and introns ±20 bp to explore BRCA1 gene mutation. If the mutation in the allele is identified from the proband in the family, it is appropriate to validate specific loci in the family using the Sanger sequencing method.

Most of the pathogenic mutations of BRCA1 are frameshift mutations and nonsense mutations caused by a single or several base changes. A large fragment rearrangement variant should be considered when no mutations are found by conventional gene sequencing in HBC/hereditary ovarian cancer families ( Schmidt et al., 2017 ). MLPA is the most commonly used method to detect large fragment rearrangement in BRCA1 ( Engert et al., 2008 ). When the polymorphic changes in the DNA of the binding site of the primers affect the binding force between the primers and the target fragment (allelic dropouts), it may lead to both false-positive and false-negative results. When a rearrangement variant is detected by an amplicon-based NGS panel, an additional MLPA assay may be considered for validation ( Gomez et al., 2009 ). The targeting RNA-seq is used to analyze the naturally occurring splicing events of eight BC and/or ovarian cancer susceptibility genes ( BRCA1, BRCA2, RAD51C, Rad51d, PTEN, STK11, CDH1, TP53 ). The results showed that the targeted RNA-seq could identify abnormal splicing events associated with BRCA1 genetic variation and successfully distinguish between complete and incomplete splicing events, which is of great significance in determining pathogenicity ( Brandao et al., 2019 ).

Prevention Strategies in BRCA1 Mutation Carriers

Female carriers of a BRCA1 mutation face a higher lifetime risk to develop BC and ovarian cancer. In general, there are three risk-reducing strategies that have been recommended for these carriers: surveillance, risk-reducing surgery, and chemoprevention. Due to comprehensive considerations, the individual risk-reducing strategy should be discussed and made in terms of several factors including the risk from the specific mutation loci, age, general health status, and the life expectancy of the patient. This risk-reducing therapy should be discussed in a shared decision-making environment with a multidisciplinary team.

Until now, risk-reducing surgeries, a risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), or a combination of both, have been considered to be most effective in preventing the onset of BC and ovarian cancer. RRM can reduce the risk of developing BC in BRCA1 carriers by more than 90% ( Meijers-Heijboer et al., 2001 ; Heemskerk-Gerritsen et al., 2013 ; Li et al., 2016 ) and even reduce mortality from any cause ( Honold and Camus, 2018 ). The psychosocial effect after RRM should not be ignored, with respect to negative impacts on body image and sexuality. Thus, the NCCN guidelines recommend that women with a BRCA1 mutation may undergo RRM with immediate bilateral breast reconstruction and multidisciplinary consultations before making treatment plans, and postoperative psychological counseling is necessary. The European Society of Medical Oncology (ESMO) ( Cardoso et al., 2019 ) and NCCN ( Esteller et al., 2000 ) of the United States stated that prophylactic RRSO may significantly reduce the risk of BC and ovarian cancer in women with BRCA1 gene mutation after the completion of reproductive needs. Several prospective clinical trials demonstrated the efficacy of selective estrogen receptor modulators ( Cuzick et al., 2013 ) (i.e., tamoxifen, raloxifene) and aromatase inhibitors exemestane ( Goss et al., 2011 ) and anastrozole ( Cuzick et al., 2014 ) for preventing BC in unselected women. However, there is limited evidence supporting the efficacy of those risk-reducing endocrine therapy options for the carriers of BRCA1 mutations. Studies failed to show the efficacy of tamoxifen ( King et al., 2001 ) or letrozole ( Pujol et al., 2020 ) on decreasing BC incidence in women with germline BRCA1 mutations.

Treatment of Breast Cancer With BRCA1 Mutation: Current Practice and Future Directions

In general, the most common treatments for BC include a combination of surgery, radiation, chemotherapy, hormone therapy, targeted therapy, and immunotherapy. The commonly used surgical treatment methods include breast-conserving surgery (BCS), and mastectomy with the option of breast reconstruction. However, whether BCS is oncologically safe for BRCA mutation carriers has remained controversial ( Cao et al., 2019 ; Davey et al., 2021 ). For BRCA1 mutation carriers, breast conservation, comprising of lumpectomy followed by whole breast radiation, was associated with higher local recurrence risk for BC patients with BRCA1 mutation; however, BRCA1 mutation was not associated with inferior survival outcomes. Since there is no prospective randomized controlled trial that directly compared BCS and ipsilateral mastectomy for BC patients with BRCA1 mutation, it should be careful to consider BCS ( Cao et al., 2019 ; Davey et al., 2021 ). Regarding the significant increased risk of developing contralateral BC ( Mavaddat et al., 2013 ), for BC patients with mutations in BRCA1 , bilateral nipple-sparing mastectomy combined with reconstruction is a reasonable option for BRCA1 mutation carriers ( Tung et al., 2020a ).

PARP Inhibitor and Metastatic Breast Cancer With BRCA1 Mutations

PARP inhibitions could induce the death of BRCA1 -deficient cells and tumors by interfering with DNA replication, playing a synthetic lethal effect ( Farmer et al., 2005 ; Lord and Ashworth, 2017 ). Olaparib and talazoparib, as PARP inhibitors, could bring improvement in progression-free survival (PFS) and tumor response rates, and likely improve overall survival for metastatic germline BRCA1- mutated, HER2-negative BC patients based on the primary results from two phase III randomized controlled trials (OlympiAD ( Robson et al., 2019 ) and EMBRACA ( Litton et al., 2020 )), respectively. Thus, they received approval from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). More recently, olaparib monotherapy ( Gelmon et al., 2021 ) and pamiparib ( Sun et al., 2021 ), also showed a promising response in patients with advanced HER2-negative BC with a germline BRCA1 mutation. Additionally, veliparib ( Somlo et al., 2017 ; Dieras et al., 2020 ; Xu et al., 2021 ), and niraparib ( Turner et al., 2021 ) are also in investigation for BRCA1 -mutated metastatic BC with modest benefit for patients. Those data revealed that the actions of different inhibitors as a PARPi are not the same. Therefore, based on the results above and studies currently under way, PARPi remain a very active area of investigation for BC with BRCA1 mutation.

Based on preliminary data, there is an ongoing trial to explore the efficacy and safety of PARP inhibitors combined with apatinib (NCT04296370). Ceralasertib, an ataxia telangiectasia and Rad3-related protein ATR inhibitor, targets DNA damage repair and cell cycle regulation and shows synergistic antitumor effects combined with olaparib in preclinical studies and a pilot clinical trial ( Mahdi et al., 2021 ).

PARP Inhibitor and Early Breast Cancer With BRCA1 Mutations

In the neoadjuvant setting, a series of clinical trials explored the role of PARP inhibitors; however, the data cannot achieve a clear conclusion. In the BrightNess trial, with the patients with germline BRCA mutation, the pathological complete response (pCR) rate was 57% in the veliparib combined with the carboplatin/paclitaxel arm, 50% in the placebo-carboplatin/paclitaxel arm, and 41% in the control paclitaxel arm ( Loibl et al., 2018a ). The difference for adding veliparib was not significant, but the trial was not powered to detect it. In GeparOLA ( Fasching et al., 2021 ), the olaparib-containing arm failed to reach its primary endpoint and had a similar pCR compared to the carboplatin-based arm (55.1% vs. 48.6%) in HER2-negative patients with germline BRCA1/2 mutation, or somatic BRCA1/2 mutation, or a high homologous recombination deficiency score. Of note, neoadjuvant single-agent talazoparib without chemotherapy showed promising antitumor activity with manageable toxicity ( Litton et al., 2021 ) in BRCA1 -mutated TNBC, which is close to standard chemotherapy in such patients based on previous studies.

In the multicentric, randomized, double-blinded, placebo-controlled phase III OlympiA trial ( Tutt et al., 2021 ), adjuvant olaparib significantly reduced the risk of invasive disease recurrence or death by 42% in high-risk HER2-negative early BC with germline BRCA1/2 mutations. Subgroup analysis showed a consistent benefit in patients with BRCA1 mutations. Importantly, the rate of central nervous system (CNS) recurrence was lower with olaparib treatment than that of placebo arm, which suggests the action of olaparib. FDA-approved adjuvant olaparib for early HER2-negative BC patients with high-risk-carrying germline BRCA1/2 mutation. The definition of high risk in BC patients was defined in Table 1 . OlympiA ( Tutt et al., 2021 ) emphasizes the need to conduct the BRCA genetic test early to allow individualized treatment, which would maximize long-term outcomes for the BC patients with germline BRCA mutations.

Definition of high-risk population in OlympiA.

Abbreviations: pCR, pathological complete response; HR, Hormone receptor; HER2, human epidermal growth factor receptor 2; CPS+EG, clinical-pathologic staging system that incorporates ER status and nuclear grading.

Platinum Salts and Early Breast Cancer With BRCA1 Mutations

Retrospective clinical studies in the neoadjuvant setting have shown that early BC patients with BRCA1 mutations are more sensitive to platinum salts ( Byrski et al., 2010 ; Arun et al., 2011 ; Saether et al., 2018 ; Holanek et al., 2019 ). However, the role of neoadjuvant platinum in patients with BRCA1 mutation is still unclear due to the conflicting data from several prospective clinical trials. GeparSixto ( Hahnen et al., 2017 ; Loibl et al., 2018b ) and CALGB 40603 ( Sikov et al., 2015 ) trials demonstrated that early TNBC patients benefit from platinum-based neoadjuvant chemotherapy with higher pCR rates than that from platinum-free neoadjuvant chemotherapy. However, results of the post-hoc exploratory subgroup analyses from GeparSixto failed to demonstrate that BRCA1 mutation could predict higher pathological response. Furthermore, the addition of platinum could yield comparably high pCR for BRCA1 mutation and wild-type patients ( Sharma et al., 2017 ). Nevertheless, pCR tended to be worse in the cisplatin- containing group than in the doxorubicin–cyclophosphamide group for BRCA carriers with early HER2-negative BC ( Tung et al., 2020b ). The BrightTNess trial demonstrated that the addition of carboplatin increased pCR ( Loibl et al., 2018a ) and improved event-free survival ( Loibl, 2021 ) compared with paclitaxel alone in unselected TNBC patients. Therefore, for germline BRCA mutation carriers with BC treated with neoadjuvant therapy, the routine addition of platinum to anthracycline and taxane-based chemotherapy is not supported. Therefore, we need more evidence to explore the role of platinum salts in early BC with BRCA mutations. Several ongoing trials are conducted to investigate the efficacy and safety of neoadjuvant platinum-containing chemotherapy or combined with olaparib in neoadjuvant therapy for operable TNBC (NCT 02978495, NCT 04664972, NCT03150576).

Platinum Salts and Metastatic Breast Cancer With BRCA1 Mutations

Germline BRCA carriers could benefit from platinum agents in the treatment with metastatic BC ( Kriege et al., 2009 ; Byrski et al., 2012 ). However, those results should be interpreted with caution due to small sample size. In a phase III trial TNT ( Tutt et al., 2018 ), in the subset of patients with BRCA - mutated metastatic BC, patients benefit more from carboplatin versus docetaxel, who yielded a greater objective response rate (ORR) and longer PFS. However, no overall survival benefit was observed. In addition, TNT trial might also be underpowered due to a small sample size for BRCA1/2 mutation carriers ( n = 55). In another small-sample-size (N = 11) single-arm trial, 6-mercaptopurine (6 MP) and methotrexate, which could selectively kill BRCA -defective cells in a xenograft model, failed to show anti-tumor activity for advanced BC with a BRCA1 mutation ( Roberts et al., 2020 ).

Resistance to Platinum-Based Chemotherapy or PARP Inhibition

PARPi-based chemotherapy has shown great promise in clinics; however, not all patients with mutations in BRCA1 or genes associated with BRCAness will respond to PARPi, as different mutations may have differing effects on the DNA double-stand break repair function and sensitivities to PARP inhibition. There is very limited understanding of what factors may affect PARPi responses in the setting of BRCA1 mutations and other BRCAness genes. It is also likely that the therapeutic implications may differ in different cancer types, further reinforcing the importance of the context in which BRCA and other HR-related genes function in these malignancies.

In addition, lots of patients acquire PARPi resistance with prolonged PARPi treatment in clinics. Resistance to platinum-based chemotherapy is also a promising predictor for resistance to PARPi, suggesting that they may share a common mechanism. The main molecular mechanisms of PARPi resistance are the cellular availability of the inhibitor, reverse mutations, homologous recombination repair restoration, and restoration of replication fork protection. Firstly, in a murine model of BRCA1 -deficient breast tumors, tumors with overexpressed drug-efflux transporter genes (Abcb1a and Abcb1b encoding for MDR1/P-gp and Abcg2) showed resistance to PARPi by influencing the cellular availability of the inhibitor. The coadministration of the MDR1 inhibitor could resensitize the tumors to the PARPi ( Rottenberg, et al., 2008 ). Secondly, somatic reversion mutations were found in cfDNA (circulating cell-free) in BC patients who acquired resistance to platinum and/or PARP inhibitors. The BRCA1 reversion mutation could restore BRCA1 function( Weigelt, et al., 2017 ). Thirdly, the fork degradation of deprotected replication forks is mediated by at least three mechanisms, which, upon loss, leads to fork protection and thus to PARPi resistance. ( Angelo et al., 2017 ). Lastly, HR reactivation is dependent on the ubiquitin E3 ligase RNF168 and the loss of 53BP1–RIF1–REV7–Shieldin axis in BRCA1 -deficient and TP53BP1-deficient cells, leading to PARPi resistance ( Nakada et al., 2012 ; Dev, et al., 2018 ). In addition, cancer stem cells (CSCs) in BRCA1 mutant TNBCs were resistant to PARP inhibition, and RAD51 protein levels and activity were elevated. ShRNA downregulated the expression of RAD51 and thereby made CSCs sensitive to PARPi. ( Liu et al., 2016 ). Therefore, RAD51 is a functional biomarker to be used in the clinic to identify PARPi-sensitive cancer patients and select the population who may respond to PARPi therapy (C Cruz, et al., 2018 ). Moreover, epigenetic modification and restoration of ADPribosylation (PARylation) lead to PARPi resistance as well. Studies show that patients with high probability of resistance to PARPi may obtain a benefit from combinatorial treatment strategies. Since PALB2–BRCA2 recruitment to DNA breaks and RAD51 recruitment to stalled forks are both ATR dependent, the combination of PARPi with ATR inhibitors is expected to overcome PARPi resistance in tumors by restoring HR or restoring fork protection. (Stephanie A Yazinski et al., 2017 ). It is of great importance to clarify the clinical relevance of the different PARPi resistance mechanisms through more large patient cohorts. These studies will pave the way for patients in the clinic to improve diagnosis, therapy decisions, and outcome.

Hormone Therapy and Breast Cancer With BRCA1 Mutations

Carriers of BRCA1 mutation are more likely to develop TNBC ( Atchley et al., 2008 ). Therefore, for those hormone receptor-positive BC patients with pathogenic BRCA1 mutations, hormone therapy is essential to delay the progression and prevent the onset of contralateral tumors. Adjuvant tamoxifen ( Narod et al., 2000 ) and aromatase inhibitors ( Gutierrez-Barrera et al., 2015 ) could significantly reduce the risk of contralateral tumors. The addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset ( Evron et al., 2019 ).

Immunotherapy and Breast Cancer With BRCA1 Mutations

Immunotherapy is an important approach for cancer treatment, and DNA repair defects are an important factor in enhancing the anti-tumor immune response. The germline BRCA1 mutation is related to the high mutation burden of TNBC, and the combination of cisplatin and PD-1/CTLA-4 antibody has a more significant tumor inhibition effect than the use of cisplatin alone ( Mouw et al., 2017 ). Therefore, the combination of immune checkpoint inhibitors and chemotherapy can effectively improve the efficacy of HR-deficient tumors. In addition, a number of clinical trials of PARP inhibitors combined with chemotherapy or immunotherapy are under way, and preliminary results show that PARP inhibitors combined with immunotherapy can enhance the killing effect of BRCA1 germline mutation BC ( Mateo et al., 2019 ; Domchek et al., 2020 ).

Following the success of previous trials, there is a series of phases two clinical trials currently ongoing with immunotherapy or targeted therapy in BC patients with germline BRCA1 mutation ( Table 2 ).

Immunotherapy or targeted therapy-based treatment in metastatic BC with BRCA mutation: ongoing clinical trials.

Beyond BRCA1 Germline Mutation

In addition to BRCA1 and BRCA2 mutations, the BC patients with BARD1, PALB2, RAD51, FANCA , ATM , ATR , and CHK2 mutations also present an HRR defect and might also share sensitivity to platinum-based drugs and PARPi (Christopher J. Lord and Ashworth, 2016 ). The above HR genes share the same cancer genetic profile and are called BRCAness ( Cai, 2020 ). All these genes’ mutations increase the sensitivity of tumor cells to PARP inhibitors, suggesting that PARP inhibitors may be effective against multiple tumors rather than specific tumors with BRCA1 mutations. TBCRC 048, a phase II study, emphasized that PARP inhibition is an effective treatment for patients with MBC and germline PALB2 or somatic BRCA1/2 mutations ( Tung et al., 2020c ). Furthermore, in treatment-naïve TNBCs, olaparib monotherapy yielded a high clinical response rate with BRCAness signature ( Eikesdal et al., 2020 ), beyond germline HR mutations (NCT02849496, NCT03990896, NCT04892693). Many similar clinical trials are underway, which will greatly expand the usage of PARP inhibitors.

BRCA1 gene is a well-known tumor suppressor gene, and germline BRCA1 mutation is closely related to the occurrence, development, and treatment of BC. With the advancement and popularization of gene sequencing technology, BRCA testing has been widely used in clinical practice. For better outcomes of BC patients with germline BRCA1 mutation, it is necessary and critical to comprehensively consider the combination of the therapies, and a multidisciplinary consultant is required to make an appropriate individualized management plan. With further exploration on the BRCA1 gene, more and more patients with BRCA1 mutations will benefit.

Author Contributions

XF carried out the design and drafted the manuscript. WT and QS articipated in the draft of the manuscript. JL and HP conceived of the study, and participated in its design and coordination and helped to drafted the manuscript. All authors read and approved the final manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2022.813457/full#supplementary-material

Abbreviations

CBR, clinical benefit rate; HDR, homologous DNA repair; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ORR, overall response rate; PFS, progression-free survival; TNBC, triple-negative breast cancer.

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Nicole Dyer-Griffith diagnosed with stage three breast cancer

IN a two-minute-eight-second video posted to Facebook on September 14, former Miss Universe Trinidad and Tobago and government senator Nicole Dyer-Griffith announced that she has been diagnosed with stage three breast cancer.

“I’m currently on my sixth round of chemotherapy, I have two more rounds to go, followed by surgery. If all goes well, we will then proceed to the final stage, which is radiation therapy.”

Sporting a shaved head and a brightly coloured African-print tube dress, Dyer-Griffith addressed viewers, saying, “I know I look a little different.”

She said she received the diagnosis earlier this year.

“The journey this far has been one of distress to discovery. I've unearthed such power, peace and perseverance. I can safely say this chapter has truly made me find unique methods of oxygenating not only myself but those who are also traversing this journey along with me.”

She expressed gratitude to her husband, political leader of the National Transformation Alliance Gary Griffith, who appeared in the video with her, as well as their son, her stepdaughters, extended family and close friends, calling them a blessing.

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• Open access
• Published: 13 September 2024

Discovery of vitexin as a novel VDR agonist that mitigates the transition from chronic intestinal inflammation to colorectal cancer

• Yonger Chen 1 , 2   na1 ,
• Jian Liang 2   na1 ,
• Shuxian Chen 3   na1 ,
• Nan Lin 3 ,
• Shuoxi Xu 2 ,
• Jindian Miao 2 ,
• Jing Zhang 2 ,
• Chen Chen 2 ,
• Xin Yuan 4 ,
• Zhuoya Xie 5 ,
• Enlin Zhu 6 ,
• Mingsheng Cai 1 ,
• Xiaoli Wei 5 ,
• Shaozhen Hou 2 &
• Hailin Tang 5  

Molecular Cancer volume  23 , Article number:  196 ( 2024 ) Cite this article

Metrics details

Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.

• Deficiency in VDR accelerates the progression from chronic colitis to colorectal cancer.

• Vitexin regulates transcription by targeting VDR and upregulating its nuclear expression.

• Vitexin induces M1 polarization of macrophages in the tumor microenvironment via the VDR/PBLD signaling pathway, mitigating the progression from chronic colitis to colorectal cancer in mice.

Introduction

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality globally, with over 20% of cases linked to chronic inflammation [ 1 ]. Colitis-associated colorectal cancer (CAC) represents a particularly aggressive subtype of CRC that occurs in patients with inflammatory bowel disease (IBD) who have been in a chronic inflammatory environment for a long time [ 2 , 3 ]. The largest cohort study in China showed that homologous recombination pathway gene mutations are another major genetic risk factor for heterogeneous clinical phenotypes of colorectal cancer [ 4 ]. Unlike sporadic CRC, which typically progresses through the adenoma-dysplasia-carcinoma sequence, CAC is characterized by the accumulation of somatic mutations that facilitate the progress transition from inflammatory mucosa to dysplasia to carcinoma [ 5 ], and patients with CAC are often diagnosed at an advanced stage and with a poor prognosis [ 6 ]. Thus far, the management of colorectal cancer has encountered substantial challenges, particularly due to the development of drug resistance in treatments targeting the disease [ 7 , 8 , 9 , 10 ]. Studies have shown that mitochondria in colorectal cancer stem cells are a target for drug resistance [ 11 ]. Inflammatory damage accelerates the onset and progression of CAC [ 12 ]. This inflammatory signaling is mediated through dynamic crosstalk between cancer cells and tumor microenvironment (TME) cells. Therefore, exploring the intrinsic connection between cancer cells and TME cells is also crucial for a better understanding of carcinogenesis.

The TME consists of various types of non-malignant stromal cells, including macrophages, neutrophils, lymphocytes, endothelial cells, and cancer-associated fibroblasts (CAFs). Tumor-associated macrophages (TAMs) play a pivotal role in tumor progression, metastasis, and recurrence following treatment [ 13 , 14 ]. The plasticity and heterogeneity of macrophages allow them to be classified along the M1-M2 polarization axis [ 15 , 16 , 17 ]. Tumor-associated macrophages usually exhibit an M2-like phenotype with pro-tumor functions, whereas M1 macrophages have anti-tumor functions. Consequently, reprogramming TAMs to adopt an M1-like phenotype represents a promising strategy to promote tumor regression [ 18 , 19 ]. Various approaches exist for selecting the M1 phenotype from TAMs or reprogramming TAMs from an M2 to an M1 phenotype, including TLR agonists, monoclonal antibodies targeting M1 phenotype suppressor proteins, and other compounds [ 20 ]. Targeted therapy usies utilizing small molecule compounds can specifically target genes in tumor cells, precisely acting on cancer cells to inhibit proliferation and reduce damage to normal cells, providing new insights for cancer treatment. Numerous studies have demonstrated that small molecule monomers derived from traditional Chinese medicine can exert therapeutic effects by targeting specific proteins. Vitexin, a flavonoid compound, has been reported to possess protective effects on the intestines. Our previous research indicated that vitexin significantly modulated macrophage polarization in the intestines of azoxymethane (AOM)/ dextran sodium sulfate (DSS) mice and exhibited protective effects on the intestines [ 21 ]. Despite significant advancements in our understanding of tumorigenesis, the complexities underlying the interactions between cancer cells and macrophages following vitexin exposure, particularly within the immune microenvironment, remain inadequately elucidated. The role of vitamin D receptors (VDR) in the pathogenesis of colorectal cancer and colitis has been well established. Notably, patients suffering from both inflammatory bowel disease and colorectal cancer often exhibit vitamin D/VDR deficiencies. Early downregulation of VDR has been observed in the onset of colitis, correlating with the development of larger and more numerous tumors in VDR-deficient models of CAC [ 22 , 23 ]. Recent investigations have indicated that vitamin D activity becomes dysregulated in advanced cancer stages, although it is known to modulate the interactions between immune and cancer cells, thereby inhibiting the production of pro-inflammatory cytokines [ 24 ]. Despite extensive research on vitamin D, critical questions regarding the biological role of intestinal VDR during the transition from colitis to CAC remain unresolved. Therefore, it is important to search for novel VDR agonists and thus explore their therapeutic role and mechanisms in inflammatory cancers. Similarly, the changes occurring in macrophages during the transition from inflammatory bowel disease to CAC are complex. Within the tumor microenvironment, both VDR and macrophages are implicated in the progression of CAC, but whether they are closely linked or functionally independent remains unclear. Considering the multiple functional roles of the VDR in the development of CAC, the cellular and molecular mechanisms by which the VDR regulates macrophages and thereby protects the host are important.

In this study, we established a mouse model of chronic colitis progressing to colorectal cancer (mid-term CAC) and demonstrated that myeloid-specific VDR knockout mice exhibit low VDR expression in the colon, which negatively correlates with the presence of M2-type macrophages. We confirmed that vitexin can target VDR and promote its transcriptional functions. We used a co-culture of macrophages and cancer cells to simulate the vitexin regulation of macrophages in the tumor microenvironment in a VDR-dependent manner and found that this regulation is achieved through the VDR/phenazine biosynthesis-like domain-containing protein (PBLD) pathway. In addition, we used a mouse model with myeloid-specific VDR knockout to study the protective effect of vitexin on VDR during inflammation and tumorigenesis. Our findings elucidate novel pathways and candidate therapeutic agents for addressing the transformation of chronic intestinal inflammation into colorectal cancer by regulating the polarization of macrophages in the tumor microenvironment.

Materials and methods

Vitexin (HPLC purity > 98%), and Calcitriol were purchased from Sigma-Aldrich. AOM were purchased from Sigma Aldrich. DSS were purchased from MP Biomedicals. Pronase were purchased from Roche. For in vitro experiments, vitexin was dissolved in DMSO and Calcitriol in water, and for in vivo studies, vitexin was dissolved in 1% carboxymethylcellulose sodium (CMC-Na) solution and Calcitriol in saline. Recombinant human protein VDR was constructed at KMD Bioscience (Tianjin, China) and recombinant human protein VDR-LBD was constructed and sequenced at DetaiBio. (Nanjing, China). APC anti-Mouse F4/80 Antibody and FITC anti-Human/Mouse CD11b Antibody were purchased from MULTI SCIENCES. PE/Cyanine7 anti-mouse CD206 (MMR) Antibody, PE anti-Nos2 (iNOS) Antibody, PE/Cyanine7 anti-human CD206 (MMR) Antibody and PE anti-human CD86 Antibody were purchased from BioLegend. PcDNA3.1(+)-VDR-3×FLAG, pGL4.10-CYP24A1 promoter, Wide-Type, pCMV3-flag-ratVDR, pCMV3-flag-ratVDR- T287A were constructed and sequenced by OBio. (Shanghai, China). Extraction kits for cell membrane and nucleus fractions were performed by beyotime (Shanghai, China).

SPF-grade Lyz2-Cre (JAX 004781) was purchased from the Jackson Laboratory, VDR fl/fl was purchased from GemPharmatech (Jiangsu, China), and Lyz2Cre-VDR fl/fl (VDR ΔMΦ ) mice were generated by crossing VDR fl/fl (VDR flox ) mice with Lyz2-Cre (Figure S2 , Supporting Information). The purchased VDR Fl/wt transgenic male mice will be co-housed with wild-type female C57BL/6J background mice at a ratio of 1:2 for mass breeding. After the newborn mice reach 2 weeks of age, they will be numbered and their tails will be clipped for genetic identification, with the identified PCR primers (Table S1 , Supporting Information).

SPF-grade male C57BL/ 6 J mice (18–22 g) were purchased from Guangzhou University of Chinese Medicine Laboratory Animal Centre. All mice were crossed with C57BL/6 for at least 10 generations. The animals were housed in the SPF-grade laboratory animal room of the Guangzhou University of Chinese Medicine and were given normal feed and free drinking water every day, with a relative humidity of 55 ± 5%, an indoor temperature of 22 ± 2 ℃, and 12 h of light. The bedding was changed every other day. The animals were acclimatized to the laboratory for at least 2 weeks before the start of the study. All animal experiments were conducted and analyzed in a blinded randomization manner.

AOM-DSS induced mid-stage colorectal cancer model

Mice were injected intraperitoneally with 10 mg/kg AOM (A5486, Sigma), followed by two cycles of 1.5% DSS in the drinking water on days 8–15 and 22–29 (referenced to previously published [ 25 ] literature but adapted). Disease progression was monitored by body weight measurements and DAI examination, and dissection was determined on day 36. The methodology for the determination of DAI is described in detail in Supplementary Table 2. At the end of the experiment, mice were executed, colon harvested and colon weight and length measured. Tumor load was quantified post-mortem by macroscopic examination of the colon.

Cell culture

THP-1 (Human Acute Monocytic Leukemia Cells) and RAW 264.7 (Mouse Mononuclear Macrophages Cells), is the most commonly used inflammatory cell model. CT26.WT (Mouse Colorectal Carcinoma Cells) are undifferentiated cells induced by N-nitroso-N-methylurea (NNMU). HCT 116 (Human Colorectal Carcinoma Cells) was isolated from male patients with colon cancer. Human Embryonic Kidney Cells (HEK) 293T cells, used as tool cells for plasmid transfection. All cells were purchased from Procell (Wuhan, China). CT26.WT, HCT116 cells were cultured in RPMI-1640 medium, and RAW264.7, HEK293T were cultured in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 100 U/ml penicillin-streptomycin. THP-1 cells were cultured in RPMI-1640 supplemented with 10% heat-inactivated FBS and 100 U/ml penicillin-streptomycin, with the addition of 0.05 mM β -mercaptoethanol, and PMA activation (Sigma, USA) THP-1 cells were used as human macrophage studies.

THP-1 cells were transfected with PBLD or control siRNA (Tsingke, China) using Lipofectamine ® 6000 Transfection Reagent (Beyotime, China) in Opti-MEM I Reduced Serum Medium for 72 h. Then, the transfected cells were used for further research.

Cellular RNA sequencing

Total RNA was extracted from THP-1 cells using TRIzol (Accurate Biotechnology, China). Library sequencing was performed by Gene Denovo Biotechnology (Guangzhou, China) on an Illumina HiseqTM 2500/4000. Bioinformatics analysis was performed using Omicsmart, a real-time interactive online platform for data analysis ( http://www.omicsmart.com ).

Gene expression profiles were analyzed by macrophage differentiation PCR arrays (Wcgene Biotech, Shanghai, China) according to the manufacturer’s protocol. β -actin and Gapdh were used as endogenous controls. Data were normalized to the reference gene based on cycle threshold (Ct) values. log2 (fold change) was calculated based on the 2 −ΔΔCt method.

Immunofluorescence staining and immunohistochemistry

The method according to a previous study [ 26 ]. Tissue wax blocks were hydrated by serial dewaxing, while cells were fixed by 4% paraformaldehyde. Then, after permeabilization with 0.05% Triton X-100 and sealing with 5% BSA, the cells were incubated with primary antibody at a dilution of 1:200 at 4 °C overnight. Fluorescently labeled secondary antibodies were used the following day. The stains were then counterstained with DAPI nuclear stain.

The operation of immunohistochemistry is carried out as described above. Following the procedures of primary antibody at a dilution of 1:200 at 4 °C overnight. After incubating with the secondary antibody the next day, DAI staining was performed. The sections were then stained with hematoxylin to visualize nuclei. The final processing steps included dehydration in graded alcohols, clearing in 100% xylene, and mounting. Images were taken with a fluorescence microscope equipped with a digital camera (Nikon, Tokyo, Japan).

Quantitative real-time PCR (qRT-PCR)

The method according to previous studies [ 27 , 28 ]. Total RNA was isolated from cells using TRIzol (Accurate Biotechnology).The concentration of total RNA was determined using a Nanodrop 2000, and 1 µg of total RNA was converted to cDNA by reverse transcription according to the PrimeScript™ RT kit instructions in a CFX96 Touch The target gene was detected in a CFX96 Touch Real-Time RCR Detection System (Bio-Rad) detector using a SYBR Green PCR master mix kit with GAPDH as an internal reference, and the primer sequences of the target gene were designed by Shanghai Sangong Biotechnology Co. The primer sequences of target genes were designed by Shanghai Bioengineering Biotechnology Company. The relative expression of target genes was calculated by using the 2- ΔΔ Ct method for quantification, and the correlation analysis was carried out. Primer sequences are shown in Supplementary Table S3 .

Western blot

The method is according to previous study [ 29 ]. In brief, proteins were isolated from cells and tissues and assayed by BCA assay. Proteins were separated by 8-12% gel electrophoresis separation kit (Beyotime, China) and transferred to polyvinylidene fluoride (PVDF) membranes using a semi-dry transfer apparatus (Bio-Rad). The membranes were blocked with 5% BSA for half an hour, and then the PVDF membranes were incubated with specific primary antibodies. The antibodies used in this study were as follows: VDR (Signalway Antibody, China, Cat#38397, 1:1000); PBLD (Proteintech, China, Cat#68317-1-Ig, 1:1000); PCNA (Affinity, China, Cat#AF0239, 1:1000); GAPDH (Affinity, China, Cat#AF7021, 1:3000); Histone (Affinity, China, Cat#BF9211, 1:3000). Immunoreactive bands were detected the following day with horseradish peroxidase-conjugated secondary antibodies and visualized by enhanced chemiluminescence. Analyses were performed using Image J analysis software and standardized against their respective controls.

Flow cytometry analysis

The method according to a previous study [ 30 ]. Cells were collected and resuspended in 500 µL of phosphate-buffered saline (PBS). Following a 30-minute incubation at room temperature with surface flow antibodies, the cells were centrifuged at 900 rpm for 4 min. The supernatant was discarded, and the cells were washed with PBS before being treated with a cell membrane-disrupting solution (Thermo Fisher, diluted 1:3) for 60 min. Afterward, the cells were washed again in PBS and incubated with polarization-associated flow antibodies for 1 h at room temperature. The cells were subsequently washed and resuspended in PBS containing 1% bovine serum albumin (BSA). Following another wash, the cells were resuspended in PBS with 1% BSA and analyzed using a NovoCyte Quanteon flow cytometer. Data were processed using NovoExpress software, with specific labeling for F4/80, CD11b, iNOS (M1), and CD206 (M2) flow-through antibodies.

VDR binding assay

The binding of vitexin to vdr was determined by several methods.

cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARST), surface plasmon resonance assay (SPR), isothermal titration microcalorimetry assay (ITC), pull-down assay and immunofluorescence co-localization assay.

For CETSA , the CETSA method was performed according to the literature [ 31 ]. THP-1 cells were inoculated in a 100 mm dish and subsequently treated with FBS-free medium containing either 0.1% DMSO or 100 µM vitexin for 2 h the following day. Post-treatment, the cells were digested with trypsin, collected, and washed before being resuspended in 1 mL of PBS supplemented with a protease inhibitor. A 90 µL aliquot of this suspension was transferred into 0.2 mL PCR tubes and subjected to heating in a PCR machine for 3 min at temperatures ranging from 43 to 67 °C. 20 µL of RIPA buffer was added to each tube, and the precipitated proteins were removed by centrifugation at 15,000 × g for 20 min at 4 ℃ after thorough mixing. Subsequent supernatant manipulation was based on general Western blot experiments.

For DARTS , the DARTS method was performed according to the literature [ 32 ]. THP-1 cells were inoculated in a 100 mm dish at an appropriate density. The following day, the cells were harvested and lysed in 500 µL of RIPA buffer containing a protease inhibitor. The resulting lysate was aliquoted equally into 5 Ep tubes and subsequently diluted tenfold in TNC buffer (50 mM Tris-HCl, pH 8.0, 50 mM NaCl, 10 mM CaCl2). The samples were then incubated with 0.1% DMSO and varying concentrations of vitexin (0, 2.5, 5, and 20 µM) for 1 h at room temperature with gentle shaking. The samples were then proteolytically cleaved with protease (2.5 µg/mL) for 10 min. Subsequent operations were based on general Western blot experiments.

For SPR experiments , the interaction between vitexin and VDR (ligand-binding domain, LBD) protein was analyzed using a Biacore T200 system (GE Healthcare, Uppsala, Sweden). Recombinant VDR (LBD) at a concentration of 40 µg/mL was used to achieve non-covalent immobilization on the surface of the activated chip. The final level of immobilized VDR-LBD was approximately 12,000 reaction units (RU). Subsequently, different concentrations of vitexin (ranging from 6.25 µM ~ to 200 µM) were injected at a flow rate of 30 µL/min, and 1× PBST (1.37 M NaCl; 26.8 mM KCL; 81 mM Na 2 HPO 4 ; 17.6 mM KH 2 PO 4 ; Ph7.2-7.4, 0.05% Tween 20) was used as the running buffer. The results were analyzed using Biacore evaluation software (T200 version 1.0) and curves were fitted in 1:1 binding mode.

For the ITC experiments , the potential interaction between vitexin and VDR (LBD) was determined using the Nano-ITC instrument (TA instruments, USA) at 25 °C. A solution of 10 µM VDR (LBD) and 200 µM vitexin were dissolved in phosphate-buffered saline (PBS) containing 5% DMSO, and stirred at 250 rpm. Twenty titrations of 2.5 µL each were performed for each titration experiment. The heat of dilution of VDR protein was determined by titrating it into PBS. Data analysis was performed using the NanoAnalyze software package (TA Instruments). The total heat exchange during each injection of VDR into the vitexin solution was fitted to an independent model with variable parameters.

For pull-down experiments , Beaver-Beads streptavidin and biotinylated vitexin were utilized in this study. Specifically, 100 µL of biotinylated vitexin glycoside was added to 10 µL of streptavidin-agarose beads and incubated for 2 h at 25 °C. Controls included biotin, unbiotinylated vitexin, and untreated beads. The full-length prokaryotic proteins of the VDR were constructed at KMD Bioscience (Beijing, China), while the prokaryotic proteins corresponding to the VDR-LBD were constructed at Detai Bioscience (Nanjing, China). And mutant VDRs (T287) of the LBD structural domain was achieved by transfecting HEK-293 cells with the encoding plasmid under Lipofect 2000. Lysates were prepared from HEK-293 cells of the constructs and then the lysates were mixed into treated streptavidin-agarose beads. The mixture was incubated at 25 °C for 3 h with gentle shaking. The samples were then spun and washed three times. The samples were boiled with 5× loading buffer and loaded onto 10% polyacrylamide gels for western blot analysis.

For immunofluorescence co-localization experiments , THP-1 cells were seeded at a density of (1 × 10 3 cells/well) were inoculated in confocal dishes, and 60 µL of biotin-vitexin (20 µM), and biotin (20 µM) intervened in the incubation for 24 h. The cyto-fluorescence staining process was started. The cells were first washed once with PBS and then fixed with 4% paraformaldehyde for 10 min. the cells were washed three times with PBS, each time for 3 min, and then closed with 5% BSA for 30 min, and diluted with FITC-avidin as well as VDR antibody, and then incubated at 4 ℃ overnight. At the end of the incubation, the cells were washed three times with PBS for 3 min each time, a fluorescent secondary antibody (Alexa Fluor Plus 594) was added, and the cells were incubated for 1 h. The nuclei were washed three times with PBS for 3 min each time, and the nuclei were stained by DAPI for 5 min. After the washing with PBS, the co-localization of the green light and the red light in the cells by laser confocal microscopy was observed.

Molecular docking

The crystal structure of the LBD structural domain (PDB:1QBD) of human VDR was obtained from the Protein Data Bank. Initial structures of ligands and receptors for docking were prepared with MGLTools 1.5.6 (The Scripps Research Institute, CA, USA). Molecular docking was performed with AutoDock Vina 1.0.2. The binding affinity of each docking pose of the oyster glycosides was recovered by the MM/GBSA method in the AmberTools18 software package [ 33 ]. Finally, key residues for protein-ligand interactions were identified based on the breakdown energy calculations for each residue.

ChIP-seq and PCR

THP-1 cells were seeded at a density of 4 × 10 6 in 100 mm dishes. After 24 h, cell attachment was induced by treatment with 100 ng/ml of phorbol 12-myristate 13-acetate (PMA). Subsequently, the cells were preincubated with either dimethyl sulfoxide (DMSO) or vitexin at a concentration of 20 µM for an additional 24 h. Chromatin immunoprecipitation (ChIP) was performed in accordance with the protocol outlined in the Thermo Fisher manual (Catalog No. 26157). Following treatment, THP-1 cells were harvested and crosslinked using 1% paraformaldehyde for 15 min, after which 125 mM glycine was added to quench the crosslinking reaction. Chromatin was sheared into 200–500 bp DNA by sonication using a Biorupter (Diagenode, UCD-200). After reserving 5.0 µl of the sheared chromatin for input to the control samples, the rest of the sheared chromatin was rotationally incubated with 5 µg of VDR (CST, USA, Cat#12550, 1:50) or IgG at 4 °C overnight. The next day, samples were added to protein A/G dynamic beads and incubated at 4 °C for 2 h. The DNA-protein complexes were washed twice with dilution buffer and then eluted from the dynamic beads with SDS buffer. Purified ChIP DNA was obtained after reverse cross-linking, proteinase K digestion, phenol/chloroform extraction, and ethanol precipitation. For ChIP-sequencing, input DNA and ChIP DNA were used to generate sequencing libraries using the Illumina DNA Sample Preparation Kit according to the manufacturer’s protocol. Briefly, the DNA samples were end-repaired, then ligated with barcode adapters, and finally amplified and purified. These DNA libraries were sequenced in an Illumina. nextSeq500 sequencer, based on the 35nt pair-end sequencing protocol. Chromatin immunoprecipitation analyses and RNA sequencing were performed with the help of Wuhan GeneBen Biotechnology Co Ltd (Wuhan, China). The promoter primers Cyp24a1 and PBLD were subsequently constructed and detected by RT-PCR.

Luciferase reporter gene assay

HEK293T cells were seeded in 6-well plates at 1 × 10 5 cells/well, wall-adhered, and transiently transfected with pGL4.10, PGL4.10-CYP24A1, pcDNA3.1-VDR-3×FLAG, and TK-luc using the Lipofectamine 3000 reagent for 6 h. The transfection solution was discarded and added to the high and medium in turn, low concentrations of vitexin (20, 10, and 5 µM) and Calcitriol (50 nM) after induction for 48 h. The transfection solution was washed twice with PBS, and the dual-luciferase reporter gene assay system was used to measure the dual-luciferase activity and to study the effect of vitexin on the transcriptional activation of the CYP24A1 promoter.

Histological assessment

Colon tissues fixed in 4% paraformaldehyde were paraffin-embedded and sectioned were used for histological analysis. The sections were stained with hematoxylin and eosin (H&E) for routine histological evaluation. For immunohistochemistry, sections were deparaffinized and hydrated. Endogenous peroxidase was blocked with 3% H 2 O 2 for 30 min. Sections were then incubated with primary antibody at a dilution of 1:100 overnight at 4 °C. Secondary antibodies were incubated at 1:200 for 1 h at room temperature and immunoreactivity was detected by diaminobenzidine (DAB). All sections were counterstained with hematoxylin.

Statistical analysis

All in vitro data represent at least three independent experiments and in vivo data represent at least six independent experiments. All experimental data are expressed as mean ± SEM (standard error of the mean). Statistical analyses were performed using GraphPad Pro Prism 8.0 (GraphPad, San Diego, CA). One-way analysis of variance (ANOVA) followed by Tukey’s test was used to analyze differences between groups of data. A p value of < 0.05 was considered a significant difference.

VDR plays an important role in the transformation of chronic intestinal inflammation-induced cancer

To systematically and comprehensively identify the key signaling molecules involved in colon cancer, we performed mRNA microarray analysis of intestinal tissues (patients or mice) with CAC and CRC with inflammatory bowel cancer and normal controls and then intersected the previously published dataset to identify differentially expressed genes (DEGs). The results showed that 136 DEGs overlapped across the four datasets. Notably, we found that Vdr expression was downregulated in intestinal tissues in these transcriptomic data (Figure S1 , Supporting Information). We next performed modeling of chronic intestinal inflammation to carcinoma [ 25 ]. As illustrated in Fig.  1 A-C, the duration of this experimental study was 36 days. Post-dissection observations revealed that, in comparison to the control group, the colons of mice in the model group exhibited significant shortening, with tumors of varying sizes emerging at the distal end of the intestine, measuring between 1 and 2 cm. This finding is consistent with atypical hyperplasia characteristic of the intermediate stage of inflammation-initiated carcinogenesis. A comprehensive assessment of the Swiss Volume of Pathology, indicated that the morphology of the terminal intestinal tissues in the model group was markedly disordered, featuring severe disruption of the colonic epithelial barrier, extensive infiltration of inflammatory cells, hyperplasia of submucosal lymphocytes accompanied by lymphoid follicle formation, and structural ambiguity. These observations suggest that the colon tissue during the intermediate modeling stage is undergoing a transition from inflammation to cancer. Genome-wide analyses, along with cellular and animal experiments, have demonstrated that VDR proteins play a role in the prevention of IBD and CRC [ 34 ]. As shown in Fig.  1 D, VDR protein expression was significantly reduced in the model group compared to the normal group, which is in line with previous studies. In addition, as shown in Fig.  1 E, the results of the heatmap indicated that the nuclear transcription gene Vdr was significantly decreased compared to the model group. In addition, polarization-related genes such as ARG1 , MRC1 , IL1 , and Nos2 were also significantly elevated, suggesting that macrophages in the middle stage of CAC were significantly polarized and infiltrated with inflammatory factors (Fig.  1 F). Meanwhile, macrophage-polarized expression of colonic fluorescence was consistent with transcriptome results.

VDR plays an important role in the transformation of chronic intestinal inflammation-induced cancer. A ) AOM/DSS induced mid-cycle CAC modeling protocol. B ) Macroscopic view of colon obtained by mid-stage CAC, Scale bar, 1 cm. C ) H&E staining of the colon, Scale bar, 200 μm. D ) Immunohistochemistry of VDR protein and statistics in colon (Scale bar, 100 μm, ** P  < 0.01). E ) Heatmap of the colon. F ) Immunofluorescence double staining of iNOS and CD206 protein in colon tissue, Scale bar, 100 μm. G ) Schematic diagram of the experimental design of VDR ΔMΦ mice. H ) Body weight in the mice, n  = 6. I ) DAI scores, n  = 6. J ) macroscopic image of the colon. K ) H&E staining of the colon. The data are presented as the mean ± SEM ( n  = 3). ## P  < 0.01 vs. WT group

Most reports suggest that intestinal conditional knockout of host VDR significantly increased tumor formation. We next explored the immunosuppressive role of VDR in the development of murine myeloid knockouts, the construction process of the knockout mouse is shown in Fig.  1 G. Western blot analysis showed that colonic tissues of VDR knockout animals displayed a loss of VDR (Figure S2 and S3 , Supporting Information), suggesting a successful knockout animal model. We then recorded changes in body weight and DAI in AOM/DSS mice (Fig.  1 H-I). As expected, VDR deletion (VDR ΔMΦ ) resulted in significantly slower body weight recovery in AOM/DSS mice, along with significantly higher DAI scores, compared to AOM/DSS controls (WT) and caged controls (VDR flox ). Further observation of micro- and macro-colonic tissues showed that the VDR ΔMΦ group showed more pronounced colonic barrier disruption and inflammatory infiltration compared to the control group (Fig.  1 J-K). These results suggest that VDR plays an important role in the transformation of chronic intestinal inflammation-induced cancer.

Vitexin targets VDR and binds amino acid motifs in its VDR-LBD region to regulate its nuclear transcription

We further investigated whether vitexin could act on the VDR. Cellular thermal shift assay (CETSA), a method for assessing the direct binding of drugs in cells, showed that vitexin, an anti-inflammatory flavonoid, increased the stability of the VDR protein in cells when subjected to a temperature gradient (Fig.  2 A). In addition, DARTS experiments showed that vitexin could stabilize the VDR, leading to its increased susceptibility to proteolysis (Fig.  2 B). These observations support the possibility that the VDR may serve as a potential cellular target for vitexin. To further confirm the direct binding of vitexin to the VDR, we synthesized a biotin-labeled vitexin probe (Fig.  2 C, Figure S4 - S6 , Supporting Information), and performed immunofluorescence experiments to explore the co-localization of the VDR and biotin-vitexin in THP-1 cells. As shown in Fig.  2 D, the VDR (red) showed a clear fluorescence overlap (yellow) with biotin-vitexin (green), suggesting a direct vitexin-VDR interaction in the cells. Altogether, these results suggest that VDR is a direct cellular target of vitexin. Therefore, we further investigated how it regulates VDR. Since the reported small-molecule VDR agonists all bind to the LBD structural domain of the VDR, we suspected that this structural domain might be the site of the vitexin interaction. To verify this experimentally, we constructed prokaryotic proteins of the full-length VDR and the LBD structural domain of the VDR (Figure S7 , Supporting Information). Immunoprecipitation pull-down confirmed that biotinylated vitexin interacts with the LBD structural domain of the VDR (Fig.  2 E, Figure S8 , Supporting Information). Next, we used surface plasmon resonance (SPR) to show that vitexin and VDR-LBD interact with an association rate constant (K D ) of 34.67 µM (Fig.  2 F). Finally, we performed isothermal titration calorimetry (ITC) analysis and found that vitexin and VDR-LBD interacted with a binding K D of 21.07 × 10 − 5 µM (Fig.  2 G). To further determine the structural stability of the binding complex of vitexin and VDR, we performed 100 ns molecular dynamics simulations to determine whether vitexin could exert allosteric modulation on VDR. The results showed that vitexin was able to tighten the VDR structural domain and adjust its conformation (Fig.  2 H-I, Figure S9 , Supporting Information). In addition, we performed energy decomposition calculations for each of the 11 docking poses in the binding site. We identified 11 residues with low average energies: ALA231, VAL234, SER235, ILE238, MET272, ASN276, THR287, ARG296, THR301, SER306, and ILE314 (Fig.  2 J). Of these, we selected THR287 for further study based on their energy values. We transfected HEK 293T cells with wild-type VDR or mutant T287A. Biotinylated vitexin pulled down the wild-type VDR but failed to interact with the mutant VDR (Fig.  2 K). These results suggest that THR287 in the LBD structural domain is essential for the interaction of VDR with vitexin.

Vitexin targets VDR and binds amino acid motifs in its VDR-LBD region. A ) Vitexin promotes the resistance of VDR to different temperature gradients as detected by CETSA in THP-1 cells. B ) Vitexin enhances the resistance of VDR to proteolytic enzymes as investigated by DARTS. C ) Chemical structure of Biotin-vitexin (Bio-vitexin). D ) Co-localization of biotin-vitexin (green) and VDR (red) by immunofluorescence, Scale bar, 10 μm. E ) Protein blotting analysis of biotin-vitexin binding to the VDR-LBD structural domain. Recombinant proteins VDR and VDR-LBD structural domains were incubated with either biotin- vitexin-loaded magnetic beads or biotin-loaded magnetic beads. The top panel shows the structure of VDR and the bottom panel shows the results of the pulled-down proteins. F ) SPR analysis showing the interaction between vitexin and recombinant VDR-LBD protein (left). Different concentrations of vitexin were added and K D values were calculated (right). G ) ITC analysis of VDR-LBD binding to vitexin, representative images are shown. Representative titration temperature plots are shown on the left, and data integration with the fitted curve (independent model) of vitexin versus VDR-LBD is shown on the right. H ) The presentative conformation of VDR protein binding with vitexin upon molecular dynamics simulation. I ) free energy landscape. J ) The left panel shows the carbon atoms of the side chains of the 11 key residues, with vitexin indicated as green and yellow bars, respectively. The right panel shows a box plot of the per-residue catabolic energy for the 11 residues. K ) Pull-down analysis of biotin-vitexin binding to mutant VDRs containing T287A. HEK 393T cells were transfected with wild-type VDR or mutants. Lysates were used to assay for binding to biotin-vitexin. The data are presented as the means ± SEM ( n  = 3). **, P  < 0.01; ns, no significance

The VDR protein is implicated in both classical and non-classical signaling pathways, exerting effects through nuclear transcription as well as cytoplasmic interactions. To further elucidate the nuclear import effects of vitexin following VDR targeting, we conducted validation experiments using murine and human-derived macrophages. As illustrated in Fig.  3 A, gradient concentrations of both vitexin and calcitriol resulted in an increase in Vdr mRNA levels. Additionally, Fig.  3 B presents immunofluorescence data demonstrating the subcellular distribution of VDR protein in the cytoplasm and nucleus following drug treatment. The results indicate that both vitexin and calcitriol significantly enhance VDR protein levels within the nucleus; however, vitexin treatment did not produce a notable increase in cytoplasmic VDR levels, instead promoting its accumulation in the nucleus. We further isolated cytoplasmic and nuclear proteins, confirming that treatment with vitexin and calcitriol facilitated the translocation of VDR proteins into the nucleus (Fig.  3 C). In order to measure transcriptional effect, the transcription factor expression plasmid VDR and its CYP24A1 promoter plasmid, were co-transfected into the HEK293T cell. As seen from Fig.  3 D, compared with the vector group, the transcription factor VDR was able to activate the target promoter CYP24A1, which was significantly increased after the stimulation by adding increasing concentrations of vitexin and calcitriol, indicating that vitexin enhances the transcriptional activity of VDR onto CYP24A1 (Figure S14 A-B, Supporting Information). Consistent with the above results, the results of ChIP-PCR showed that the assay results illustrated that both vitexin and calcitriol significantly elevated the expression of CYP24A1 (Fig.  3 E). The above experiments confirmed that vitexin binds to amino acid motifs in the VDR-LBD region to enhance the nuclear translocation of VDR, and increases its transcriptional activities.

Vitexin promotes nuclear translocation of VDR protein in macrophages and regulates nuclear transcription. Both RAW264.7 and THP-1 cells were treated with different concentrations of vitexin and Calcitriol. A ) Gene levels of VDR in RAW264.7 cells (top) and THP-1 cells (bottom) were detected by RT-PCR. B ) Immunofluorescence was used to examine the levels of VDR in the nucleus and cytoplasm, RAW264.7 cells (left) and THP-1 cells (right). Scale bar, 10 μm. C-D ) Western blot was used to examine the levels of VDR in the nucleus and cytoplasm. E ) Detection of transcription factor VDR against CYP24A1 promoter activity using dual luciferase in HEK293T cells. F ) ChIP-PCR amplification showing VDR activity against the promoter of CYP24A1. The data are presented as the means ± SEM ( n  = 3). *, P  < 0.05; **, P  < 0.01; ns, no significance

In the tumor microenvironment, vitexin promotes VDR entry into the nucleus

We subsequently investigated the role of vitexin within the tumor microenvironment. As illustrated in Fig.  4 A, we utilized bone marrow-derived macrophages (BMDMs) co-cultured with the homologous intestinal cancer cell line CT26 to simulate the tumor microenvironment for subsequent intervention experiments. Figure  4 B demonstrates that following co-culture, the expression of the Vdr gene in the simulated tumor microenvironment was significantly diminished compared to the control group, which aligns with the observed reduction of colon VDR levels in the animal model. PCR analysis revealed a marked decrease in Vdr gene expression after co-culture relative to the normal group; however, treatment with vitexin resulted in a dose-dependent increase in Vdr expression (Fig.  4 C). In addition, our results demonstrated that the VDR levels in the cytoplasm and nucleus were reduced after co-culture when compared to the normal group and that the VDR protein in the nucleus was increased in a concentration-dependent manner after the treatment with of vitexin (Fig.  4 D). These results were further confirmed by immunofluorescence (Fig.  4 E). Together our results suggest that the expression of VDR is significantly reduced in the tumor microenvironment and that the level of VDR in the nucleus increased significantly following treatment with of vitexin.

In the tumor microenvironment, vitexin promotes the nuclear translocation of VDR. A ) After 48 h incubation with vitexin, CT26 was co-cultured with BMDM for 24 h, which was at the transwell insert, and CT26 was located at the bottom of the cell plate. The experiments related to this section are all co-culture assays. B ) Left: RNA-seq analysis of THP-1 cells (THP-1 and HCT116) co-cultured with or without treatment with vitexin of differential genes ( n  = 3). Right: volcano plot of differential gene enrichment. C ) Gene levels of VDR in BMDM cells (top) and THP-1 cells (bottom) were detected by RT-PCR. D ) Western blot was used to examine the levels of VDR in the nucleus and cytoplasm. E ) Immunofluorescence was used to examine the levels of VDR in the nucleus and cytoplasm. Scale bar, 10 μm. The data are presented as the means ± SEM ( n  = 3). # , P  < 0.05; ## , P  < 0.01; *, P  < 0.05; **, P  < 0.01; ns, no significance

Vitexin regulates polarization in macrophages in the tumor microenvironment, dependent on VDR

Previous study have confirmed that vitexin upregulates the expression of the M1 type of macrophages in intestinal tissues thereby mitigating intestinal cancer [ 21 ]. However, the impact of vitexin on macrophage regulation during the transition from chronic intestinal inflammation to cancer has not been demonstrated. To address this gap, we employed a co-culture system of tumor cells and macrophages to simulate the tumor microenvironment, allowing for a more detailed investigation of the regulatory effects of vitexin on macrophages within this context (Fig.  5 A). As shown in Fig.  5 B, after treatment with vitexin, we detected macrophage-related genes by real-time PCR and compared the differentially expressed genes in the model or vitexin. As shown in the heatmap, the mRNA levels of CD163 , IL1B , CCL2 , IL6 , and TNF were significantly increased, while the mRNA level of MRC1 was significantly decreased, suggesting that vitexin promotes M1 polarization of macrophages in the tumor microenvironment. In addition, we examined the mRNA levels of Nos2 , Ccl-2 , Il-1b , and Il-6 in RAW264.7, and the results were consistent with the above trend (Figure S13 , Supporting Information). Consistent with the PCR results, the results of flow cytometry also showed that in the tumor microenvironment, vitexin regulated macrophage M1 polarization in a dose-dependent manner, while M2-polarised macrophages were significantly decreased (Fig.  5 C-D). Next, we used VDR knockdown macrophages to reverse validate the role of vitexin in regulating macrophages (Fig.  5 E). It was found by flow cytometry results (Fig.  5 F-G) that the macrophage-regulating effect of vitexin was eliminated in the VDR-knockdown cell model, however, the control treatment group was expressed consistent with the above results. Meanwhile, there was no significant change in the mRNA levels of Nos2 and Arg-1 by vitexin in BMDM cells with VDR knocked down (Fig.  5 H), suggesting that vitexin could regulate macrophage polarization but is dependent on VDR.

Vitexin regulates polarization in macrophages in co-culture, dependent on VDR. A ) Schematic diagram of the in vitro Transwell-based coculture system. B ) Heatmap of gene expression levels detected in macrophage arrays of co-cultured THP-1 cells for 24 h with or without vitexin treatment ( n  = 3 each). C ) Data are presented as representative FACS plots. D ) Flow cytometry analysis of iNOS or CD206 levels in BMDM cells from WT mice. E ) Western blot detection of VDR expression in BMDM from WT, VDR flox , and VDR ΔMΦ . F ) Flow cytometry analysis of iNOS or CD206 levels in BMDM cells. G ) Data are presented as representative FACS plots and in summary plots. H ) The levels of Nos2 and Arg-1 mRNA. The data are presented as the mean ± SEM ( n  = 3). *, P  < 0.05; **, P  < 0.01; ns, no significance

Vitexin regulates macrophage polarization in the tumor microenvironment via the VDR/PBLD pathway

Our findings suggest that Vitexin can regulate macrophage polarization through VDR protein. Next, we further explored which genes are regulated by VDR to regulate macrophage polarization. Co-cultured THP-1 cells using ChIP-Seq data are shown with high-resolution peaks identified in the read density (Fig.  6 A-B, Figure S14 C-D, Supporting Information). Guided by the ChIP-Seq results, further ChIP-PCR experiments were performed to confirm the binding regions. A series of primers were designed for the genomic fragments surrounding the transcription start site. Real-time fluorescence quantitative PCR analysis of immunoprecipitated DNA showed that the P1 (-310/-290 bp) and P2 (-327/-313 bp) fragments were the most enriched (Fig.  6 C), suggesting that the P1 and P2 fragments may contribute to the vitexin-regulated VDR regulation of PBLD transcription. Based on the ChIP results, a series of luciferase reporter genes driven by different PBLD gene fragments were constructed. Based on bioinformatics analysis, we deleted two VDRE sites in specific intervals of the PBLD promoter and examined the effect of VDR on the transcriptional activity of the PBLD promoter (Fig.  6 D). Mutation 2 significantly attenuated the enhancing effect of VDR, whereas mutation 1 had no effect (Fig.  6 E). These results suggest that VDR can enhance PBLD transcription by directly binding to the P1 fragment of the PBLD promoter. The VDR was significantly increased following stimulation with vitexin, indicating that vitexin may enhance the activation of the PBLD promoter by VDR. Previous studies have demonstrated that epithelial PBLD plays a role in mitigating intestinal inflammatory responses and enhancing intestinal barrier function, potentially through the inhibition of the NF-κB signaling pathway [ 35 ]. However, whether it affects macrophage polarization has not been reported. Weknocked down the PBLD protein in THP-1 cells (Fig.  6 F) and analyzed the effects by flow cytometry and PCR. The results showed that the ability to regulate macrophages disappeared in the siPBLD group compared with the control group after vitexin treatment (Fig.  6 G-H). Meanwhile, there was no significant change in the mRNA levels of iNOS2 and ARG-1 by vitexin in THP-1 cells with VDR knocked down (Fig.  6 I). Overall, the regulation of macrophage polarization by vitexin in the tumor microenvironment is dependent on the VDR-PBLD pathway.

Vitexin regulates macrophage polarization in the tumor microenvironment via the VDR/PBLD pathway. A ) Schematic diagram of the in vitro Transwell-based coculture system. B ) Binding maps of VDR to the PBLD gene were analyzed from ChIP-Seq data in the control and vitexin groups and visualized by IGV software. C ) The abundance of gene fragments in the input and immunoprecipitates was evaluated using designated primers through real-time PCR, and the position of the primers was detected by ChIP. D ) Schematic representation of the PBLD promoter containing three VDREs, with the promoter’s mutation strategy shown in the figure. E ) Transcriptional regulatory activity of VDR on full-length PBLD promoter and doubly VDRE-mutated PBLD promoter in HEK293T cells with or without Vitexin treatment measured by dual-luciferase reporter gene assay. F ) Western blot assay for VDR expression. G ) Flow cytometry analysis of CD86 and CD206 levels. Data are presented as representative FACS plots. H ) Statistical results of macrophage typing. I ) mRNA levels of INOS and ARG-1. Data are expressed as SEM ± mean ( n  = 3). # , P  < 0.05; ## , P  < 0.01; *, P  < 0.05; **, P  < 0.01; ns, no significance

In vivo, vitexin mitigates the transition from chronic intestinal inflammation to cancer by modulating macrophage polarization and is dependent on the VDR/PBLD pathway

The above results in vitro demonstrated that vitexin modulates the VDR/PBLD pathway to regulate macrophage polarization in the tumor microenvironment. We constructed mid-CAC mice and administered vitexin intervention. As shown in Fig.  7 A-B, all mice in the mid-stage CAC group had significantly decreased body weight compared with the normal group. In animals with normal macrophage VDR expression (VDR flox ), the body weights of animals in both calcitriol and vitexin intervention groups were significantly increased, however, in animals with macrophage VDR deletion (VDR ΔMΦ ), administration of the intervention groups did not have an effect, and the body weights of the animals were not affected compared to the CAC group. As shown in Fig.  7 C, in the VDR flox group, the body weight DAI of mice in the mid-term CAC group was significantly increased compared to the normal group, but the DAI was significantly decreased after intervention with both calcitriol and vitexin. However, in the VDR ΔMΦ group, the administered intervention group did not have an intervention effect, and the animals’ DAI was not changed compared with the CAC group. As shown in Fig.  7 D, compared with the normal group, the colons of mice in the model group had different degrees of shortening, swelling, and a little tumor-like growth. As shown in Fig.  7 E-F, in the VDR flox group, the length of the colon was significantly longer and the thickness was significantly decreased after the treatment with calcitriol and vitexin compared with the model group. The number of tumors was significantly reduced after calcitriol treatment, but there was no significant difference for vitexin. In addition, as shown in the colon pathogram (Fig.  7 G), the inhibitory effect of vitexin on the development of colorectal cancer was not significant in the VDR ΔMΦ group. This suggests that vitexin inhibits colorectal cancer development through VDR. In the VDR ΔMΦ group, there was a loss of tissue morphology in the marginal zone of colorectal cancer, with disturbed cell arrangement, necrosis, and hyperplasia. In the VDR flox group, the intervention of vitexin was able to reduce the hyperplasia of the cancerous zone and improve the tissue morphology, whereas the improvement of the cancerous zone by vitexin was not significant in the VDR ΔMΦ group, which indicated that the improvement of cancerous cell hyperplasia by vitexin in the cancerous zone relied on the VDR proteins. We employed multi-immunohistochemistry techniques, as illustrated in Fig.  7 H, to analyze colonic tissues from normal mice. The results indicated that the normal group exhibited abundant expression of VDR proteins, while the phenotypic expression of macrophage cells was notably low. In contrast, macrophages in the model group displayed significant polarization and markedly reduced levels of VDR compared to the normal group. However, following vitexin administration, there was a significant increase in both VDR and CD163 levels, suggesting that vitexin upregulates VDR protein and modulates macrophage polarization towards the M1 phenotype. Consistent with these findings, western blot analysis revealed that the expression of PBLD and PCNA proteins was significantly decreased in the CAC group compared to the normal group. Notably, after vitexin treatment, the expression levels of PBLD and PCNA proteins in the colon tissues of unknocked-out VDR mice approached those observed in normal mice (Fig.  7 I-J). However, for the tissues of mice with knockout VDR, the above proteins did not change significantly after vitexin treatment (Fig.  7 I-J). In conclusion, vitexin mitigates the transition from chronic intestinal inflammation to cancer by modulating macrophage polarization and is dependent on the VDR/PBLD pathway.

Vitexin mitigates the transition from chronic intestinal inflammation to cancer by modulating macrophage polarization and is dependent on the VDR/PBLD pathway. A ) Flow chart of drug administration. B ) Graph of body weight changes (The data are presented as the means ± SEM ( n  = 6). In the VDR flox group, ## P  < 0.01 compared with the NC group and ** P  < 0.01 compared with the CAC group.). C ) DAI score. D ) Tumor number. E ) Colon length (left), colon thickness (right). F ) Macroscopic view of colon, Scale bar, 1 cm. G ) H&E staining of the colon, Scale bar: 1000 μm and 200 μm, n  = 3). H ) Multicolour immunohistochemistry of colon tissue (VDR-green, F4/80 red, CD86 pink, CD163 rose. Scale bar, 500 μm, n  = 3). I-J ) The expression of PBLD and PCNA proteins and statistical plots ( n  = 3). The data are presented as the means ± SEM ( n  = 6). # P  < 0.05, ## P  < 0.01;* P  < 0.05, ** P  < 0.01; ns, no significance

Chronic colitis is recognized as a significant risk factor for the development of colitis-associated cancer, which typically progresses through a sequence of inflammation, typical hyperplasia, and subsequent cancerization. This progression involves a transition of the lesion microenvironment from an inflammatory state to a tumor-promoting microenvironment. In this study, we specifically targeted the VDR to modulate macrophage polarization, demonstrating that vitexin can inhibit the transition from chronic colitis to CAC. Our findings indicate that vitexin binds to the VDR protein, thereby preventing the differentiation of macrophages into the M2 phenotype and preserving the cytotoxic effects of inflammatory cytokines produced by M1-type macrophages. In vitro co-culture experiments revealed that vitexin increased the proportion of M1-type macrophages, supporting its anti-cancer properties. Furthermore, we employed myeloid-specific VDR gene knockout mice to elucidate the critical role of VDR in the mid-term progression of CAC and to confirm the targeting of VDR by vitexin. These key findings are illustrated in the graphical abstract.

One of the most important contributions of this study may be the discovery of a natural product - vitexin, which is a novel VDR agonist. Vitexin, as a flavonoid active substance, has been reported to have therapeutic effects on many cancers, including breast cancer, cervical cancer, and many other cancers [ 36 , 37 , 38 ]. Our previous studies have also confirmed that vitexin can alleviate the disease in UC and CAC mice, suggesting that vitexin may have a broad effect on cancers associated with the evolution of colitis [ 21 , 39 ]. However, the molecular mechanisms and targets of vitexin remain unknown, limiting the application of vitexin.

VDR, a nuclear receptor transcription factor, has been investigated in clinical and basic studies for its important role in colitis and colorectal cancer [ 40 , 41 , 42 , 43 ]. Studies have correlated vitamin D with survival and mortality in colorectal cancer, and in a large group of CRC patients, higher VDR expression in tumor stromal fibroblasts was associated with longer survival [ 44 ]. In the present study, it was also confirmed that mid-stage CAC mice with VDR on the table of CAC mice deficient in VDR showed more severe colon lesions and accelerated their cancerous process compared to control mice. These results suggest that VDR is a potential therapeutic target. However, one of the most promising vitamin D analogs, seocalcitol, has not demonstrated efficacy in phase II clinical trials [ 45 ]. Recent findings suggest that the relationship between elevated vitamin D levels and a reduced risk of colorectal cancer is not universally supported. Additionally, systemic activation of vitamin D signaling poses a potential risk of hypercalcemia, which can lead to severe toxicity. Notably, this study identifies vitexin as a novel agonist of the vitamin D receptor (VDR), demonstrating its ability to bind directly to the ligand-binding domain of VDR. The interaction between vitexin and VDR is significantly influenced by the residue THR-287 within the VDR structural domain, which may facilitate the design and development of new small-molecule VDR agonists. Furthermore, our findings indicate that vitexin markedly upregulates the transcription of VDR’s classical target gene, Cyp24a1. However, the implications of vitexin on the overall targeting of VDR during the CAC process, following VDR’s translocation to the nucleus, warrant further investigation.

Previous studies have shown that vitexin can alleviate the condition of CAC mice by regulating the polarization of macrophages, but its mechanism has not been thoroughly studied. As a novel VDR agonist, it is unknown whether vitexin is related to macrophage polarization. Therefore, we used an in vitro co-culture method to simulate the regulatory effect of vitexin on macrophages in the tumor microenvironment. The results found that vitexin can upregulate the content of VDR in the nucleus of macrophages, promote its entry into the cell nucleus, upregulate the polarization of M1-type macrophages, and downregulate the polarization of M2-type macrophages. However, when we extracted VDR knockout cells for further verification, we found that in macrophages with VDR knockout, vitexin could not exert its regulatory effect on macrophage polarization, indicating that the regulation of vitexin on macrophage polarization depends on VDR protein. Recent studies have confirmed that VDR-deficient keratinocyte-derived exosome miR-4505 promotes macrophage polarization towards the M1 phenotype, and that VDR can mediate hepatic ischemia-reperfusion injury by regulating M2 macrophage polarization through autophagy [ 46 , 47 ]. However, how vitexin affects VDR and thus regulates macrophage polarization is not yet known.

Genomics and proteomics data have shown that PBLD expression is deficient in a variety of tumors. PBLD is expressed in the liver, stomach, mammary gland, kidney, and intestine, and acts as a tumor suppressor in gastric carcinoma [ 48 ], hepatocellular carcinoma [ 49 , 50 ], and breast cancer [ 51 ]. acting as a tumor suppressor. The inhibitory role of PBLD in cancer is relatively clear; however, little is known about the role of PBLD in macrophage polarization, especially in CAC. A previous study demonstrated that PBLD levels were significantly reduced in UC and that PBLD expression levels were negatively correlated with UC severity, inhibiting NF-κB and epithelial-mesenchymal transition signaling pathways and acting as a tumor suppressor [ 35 ]. We report, for the first time, that the VDR directly binds to the − 310/-290 promoter region of the PBLD gene, thereby promoting its transcription and expression. Following treatment with vitexin, we observed a significant increase in the transcriptional expression of PBLD, indicating that vitexin enhances PBLD expression. Subsequently, we knocked down PBLD expression in THP-1 cells within the tumor microenvironment and found that the regulatory effect of vitexin on macrophage polarization was abolished. These findings demonstrate that vitexin can modulate macrophage polarization in the tumor microenvironment, with this effect being dependent on the VDR/PBLD signaling pathway.

In this study, we generated bone marrow-specific VDR gene knockout mice, which demonstrated an accelerated progression of colorectal cancer. These findings provide compelling evidence that VDR may serve as a potential target for preventing the transition from colitis to colorectal cancer. Notably, we observed that the absence of VDR in colitis-associated colorectal cancer (CAC) mice during mid-term treatment with vitexin did not yield therapeutic effects, nor did we detect any modulation of macrophage polarization by vitexin. A limitation of this study may be the lack of evaluation of VDR expression in specific intestinal macrophage populations. Although VDR expression in the intestine is relatively low, its expression in intestinal macrophages is significant, underscoring VDR’s critical role in intestinal immunity.

In conclusion, our findings indicate a significant reduction in the expression of VDR protein in mid-term CAC mice, with the absence of VDR protein appearing to accelerate the progression of CAC. This acceleration is likely attributable to alterations in macrophage polarization. Vitexin has been shown to directly target VDR, binding to the VDR-LBD structural domain, which facilitates its translocation into the cell nucleus. This process subsequently regulates the transcription of PBLD and influences macrophage polarization. These results underscore the direct targeting capability of vitexin and highlight the critical role of VDR as a key pathogenic factor in the transition from colitis to colorectal cancer. Furthermore, our study supports the potential for future research and the application of vitexin in preventing the progression from colitis to colorectal cancer.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Azoxymethane

Bone marrow-derived macrophage

Colitis associated cancer

Cellular heat transfer assay

Colorectal cancer

Drug affinity responsive target stability

Dextran sulfate sodium salt

Isothermal Titration Calorimetry

Phenazine biosynthesis like protein domain

Surface plasmon resonance assay

Tumor microenvironment

Vitamin D receptors

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This work was supported by the Open Subjects of State Key Laboratory of Dampness Syndrome of Chinese Medicine jointly established by the Ministry of Provincial Affairs of the People’s Republic of China; National Natural Science Foundation of China (82304905, 82272326); Natural Science Foundation of Guangdong Province (2023A1515011729, 2022A1515012408); Foundation and Applied Basic Research Fund Project of Guangdong Province (2021B1515140045 and 2021B1515140050), Guangzhou Science and Technology Bureau (202102080643), Science and Technology Program of Guangzhou (202002020032), The core technology project in the field of biological industry (2021ZD006), Regional Union Fund-Regional Nurturing Project (2021B1515140065), and Science and technology project in key fields of Nansha District (2022ZD004), the Open Project of State Key Laboratory of Respiratory Disease (SKLRD-OP-202202 and SKLRD-OP-202317); the Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (JCXKJS2022A11).

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Yonger Chen, Jian Liang and Shuxian Chen contributed equally to this work.

Authors and Affiliations

School of Basic Medical Sciences, State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University; The Affiliated Panyu Central Hospital of Guangzhou Medical University; Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 511436, China

Yonger Chen & Mingsheng Cai

State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China

Yonger Chen, Jian Liang, Shuoxi Xu, Jindian Miao, Jing Zhang, Chen Chen & Shaozhen Hou

Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China

Shuxian Chen & Nan Lin

Department of Pharmacy, The Second Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, 510120, China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research, Center for Cancer Sun Yat-Sen University Cancer Center Guangzhou, Guangzhou, 510060, China

Zhuoya Xie, Xiaoli Wei & Hailin Tang

Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China

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Contributions

Y. C., J. L and S. C. designed, performed, and analyzed experiments, and wrote the manuscript. N. L., and X.S. designed and analyzed experiments. J.Z. and C. C. designed image analysis and provided intellectual input. Y.C. and X.Y. designed and performed statistical and image analysis. Z. X., M. C. and E. Z. assisted with image acquisition and designed image analysis. M. C., S. W., S. H. and H. T. directed the study, designed and analyzed experiments, and wrote the manuscript.

Corresponding authors

Correspondence to Mingsheng Cai , Xiaoli Wei , Shaozhen Hou or Hailin Tang .

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Chen, Y., Liang, J., Chen, S. et al. Discovery of vitexin as a novel VDR agonist that mitigates the transition from chronic intestinal inflammation to colorectal cancer. Mol Cancer 23 , 196 (2024). https://doi.org/10.1186/s12943-024-02108-6

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DOI : https://doi.org/10.1186/s12943-024-02108-6

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