Breast Cancer Research最新文献

{"title":"Retraction Note: Association of Life's Essential 8 cardiovascular health with breast cancer incidence and mortality according to genetic susceptibility of breast cancer: a prospective cohort study.","authors":"Yan Zhao, Yang Song, Xiangmin Li, Ayao Guo","doi":"10.1186/s13058-025-02021-w","DOIUrl":"https://doi.org/10.1186/s13058-025-02021-w","url":null,"abstract":"","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"56"},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning prediction of HER2-low expression in breast cancers based on hematoxylin-eosin-stained slides.","authors":"Jun Du, Jun Shi, Dongdong Sun, Yifei Wang, Guanfeng Liu, Jingru Chen, Wei Wang, Wenchao Zhou, Yushan Zheng, Haibo Wu","doi":"10.1186/s13058-025-01998-8","DOIUrl":"https://doi.org/10.1186/s13058-025-01998-8","url":null,"abstract":"<p><strong>Background: </strong>Treatment with HER2-targeted therapies is recommended for HER2-positive breast cancer patients with HER2 gene amplification or protein overexpression. Interestingly, recent clinical trials of novel HER2-targeted therapies demonstrated promising efficacy in HER2-low breast cancers, raising the prospect of including a HER2-low category (immunohistochemistry, IHC) score of 1 + or 2 + with non-amplified in-situ hybridization for HER2-targeted treatments, which necessitated the accurate detection and evaluation of HER2 expression in tumors. Traditionally, HER2 protein levels are routinely assessed by IHC in clinical practice, which not only requires significant time consumption and financial investment but is also technically challenging for many basic hospitals in developing countries. Therefore, directly predicting HER2 expression by hematoxylin-eosin (HE) staining should be of significant clinical values, and machine learning may be a potent technology to achieve this goal.</p><p><strong>Methods: </strong>In this study, we developed an artificial intelligence (AI) classification model using whole slide image of HE-stained slides to automatically assess HER2 status.</p><p><strong>Results: </strong>A publicly available TCGA-BRCA dataset and an in-house USTC-BC dataset were applied to evaluate our AI model and the state-of-the-art method SlideGraph + in terms of accuracy (ACC), the area under the receiver operating characteristic curve (AUC), and F1 score. Overall, our AI model achieved the superior performance in HER2 scoring in both datasets with AUC of 0.795 ± 0.028 and 0.688 ± 0.008 on the USCT-BC and TCGA-BRCA datasets, respectively. In addition, we visualized the results generated from our AI model by attention heatmaps, which proved that our AI model had strong interpretability.</p><p><strong>Conclusion: </strong>Our AI model is able to directly predict HER2 expression through HE images with strong interpretability, and has a better ACC particularly in HER2-low breast cancers, which provides a method for AI evaluation of HER2 status and helps to perform HER2 evaluation economically and efficiently. It has the potential to assist pathologists to improve diagnosis and assess biomarkers for companion diagnostics.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"57"},"PeriodicalIF":7.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central and peripheral adiposity and premenopausal breast cancer risk: a pooled analysis of 440,179 women.","authors":"Minouk J Schoemaker, Taylor Ellington, Hazel B Nichols, Lauren B Wright, Michael E Jones, Katie M O'Brien, Clarice R Weinberg, Hans-Olov Adami, Laura Baglietto, Kimberly A Bertrand, Yu Chen, Jessica Clague DeHart, A Heather Eliassen, Graham G Giles, Serena C Houghton, Victoria A Kirsh, Roger L Milne, Julie R Palmer, Hannah Lui Park, Thomas E Rohan, Gianluca Severi, Xiao-Ou Shu, Rulla M Tamimi, Lars J Vatten, Elisabete Weiderpass, Walter C Willett, Anne Zeleniuch-Jacquotte, Wei Zheng, Dale P Sandler, Anthony J Swerdlow","doi":"10.1186/s13058-025-01995-x","DOIUrl":"https://doi.org/10.1186/s13058-025-01995-x","url":null,"abstract":"<p><strong>Background: </strong>Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics.</p><p><strong>Methods: </strong>We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0-11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers.</p><p><strong>Results: </strong>All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90-0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95-1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10-1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71-0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03-1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15-1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17-1.84).</p><p><strong>Conclusions: </strong>Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"55"},"PeriodicalIF":7.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacovigilance study of adverse reactions of anti-HER-2 drugs for the treatment of HER-2-positive breast cancer based on the FAERS database.","authors":"Jinming Han, Xiaohan Zhai, Xufeng Tao, Yunming Li, Ziqi Zhao, Zhan Yu, Deshi Dong, Shilei Yang, Linlin Lv","doi":"10.1186/s13058-025-02013-w","DOIUrl":"https://doi.org/10.1186/s13058-025-02013-w","url":null,"abstract":"<p><strong>Objective: </strong>There are three categories of drugs that treat human epidermal growth factor receptor type 2 (HER-2) positive breast cancer: monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs). The purpose of this study is to analyze and compare the adverse reactions of three classes of anti-HER-2 drugs to various body systems in patients based on the FDA Adverse Event Reporting System (FAERS).</p><p><strong>Methods: </strong>All data reports were extracted from the FAERS between 2004 and 2024. Data mining of adverse events associated with anti-HER-2 drugs was carried out using disproportionality analysis. A multivariate logistic regression analysis was conducted to explore the risk factors associated with AEs leading to hospitalization.</p><p><strong>Results: </strong>A total of 47,799 patients were screened for the three classes of drugs, among which ADC drugs caused the largest proportion of deaths. MAb has the strongest ADR signals associated with \"cardiac disorders\". Moreover, trastuzumab was associated with a greater risk of cardiotoxicity. Logistic regression analysis revealed that the treatment with mAbs should be wary of serious adverse reactions in \"infections and infestations\" and \"metabolism and nutrition disorders\". Moreover, \"endocrine disorders\" were the factor associated with the highest risk of prolonged hospitalization due to trastuzumab deruxtecan (T-DXd). The safety of tucatinib among TKI drugs is greater than that of other drugs.</p><p><strong>Conclusion: </strong>In general, from the perspective of the effects of the three classes of drugs on the various body systems of patients, we should focus on mAb-associated \"cardiac disorders\", ADC-associated \"hepatobiliary disorders\", \"respiratory, thoracic and mediastinal disorders\", and TKI-associated \"gastrointestinal disorders.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"54"},"PeriodicalIF":7.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stem cell markers in benign breast tissue.","authors":"Lusine Yaghjyan, Yujing J Heng, Brian R Sardella, Divya Murthy, Matt B Mahoney, Bernard Rosner, Kornelia Polyak, Maisey Ratcliff, Rulla M Tamimi","doi":"10.1186/s13058-025-02002-z","DOIUrl":"10.1186/s13058-025-02002-z","url":null,"abstract":"<p><strong>Background: </strong>The insulin-like growth factor (IGF) pathway is implicated in a naturally occurring process of tissue remodeling during which cells acquire stem cell-like characteristics. We examined associations of circulating IGF-1 and IGF binding protein-3 (IGFBP-3) with expression of CD44, CD24, and ALDH1A1 stem cell markers in benign breast biopsies.</p><p><strong>Methods: </strong>This study included 151 cancer-free women with incident biopsy-confirmed benign breast disease and blood samples within the Nurses' Health Study II. The data on reproductive and other BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using QuPath, and expressed as % of cells that stain positively for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of plasma IGF-I and IGFBP-3 (continuous log-transformed and quartiles) with log-transformed expression of each marker (in epithelium and stroma), adjusted for BCa risk factors.</p><p><strong>Results: </strong>In multivariate analysis, continuous circulating IGF-1 and IGFBP-3 measures were not associated with the continuous expression of any of the markers in the epithelium or stroma. Women whose IGFBP-3 levels were in the top quartile appeared to have lower expression of stromal CD24 compared to those in the lowest quartile (β = - 0.38, 95% CI - 0.69, - 0.08, p-trend = 0.06).</p><p><strong>Conclusions: </strong>Higher circulating IGFBP-3 levels were associated with lower stromal CD24 expression in benign breast tissue. Our findings provide indirect evidence of the inducing effect of IGF pathway on epithelial-to-mesenchymal transitions and stem cell activity in the breast.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"53"},"PeriodicalIF":7.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11978140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early prediction of neoadjuvant therapy response in breast cancer using MRI-based neural networks: data from the ACRIN 6698 trial and a prospective Chinese cohort.","authors":"Siyao Du, Wanfang Xie, Si Gao, Ruimeng Zhao, Huidong Wang, Jie Tian, Jiangang Liu, Zhenyu Liu, Lina Zhang","doi":"10.1186/s13058-025-02009-6","DOIUrl":"10.1186/s13058-025-02009-6","url":null,"abstract":"<p><strong>Background: </strong>Early prediction of treatment response to neoadjuvant therapy (NAT) in breast cancer patients can facilitate timely adjustment of treatment regimens. We aimed to develop and validate a MRI-based enhanced self-attention network (MESN) for predicting pathological complete response (pCR) based on longitudinal images at the early stage of NAT.</p><p><strong>Methods: </strong>Two imaging datasets were utilized: a subset from the ACRIN 6698 trial (dataset A, n = 227) and a prospective collection from a Chinese hospital (dataset B, n = 245). These datasets were divided into three cohorts: an ACRIN 6698 training cohort (n = 153) from dataset A, an ACRIN 6698 test cohort (n = 74) from dataset A, and an external test cohort (n = 245) from dataset B. The proposed MESN allowed for the integration of multiple timepoint features and extraction of dynamic information from longitudinal MR images before and after early-NAT. We also constructed the Pre model based on pre-NAT MRI features. Clinicopathological characteristics were added to these image-based models to create integrated models (MESN-C and Pre-C), and their performance was evaluated and compared.</p><p><strong>Results: </strong>The MESN-C yielded area under the receiver operating characteristic curve (AUC) values of 0.944 (95% CI: 0.906 - 0.973), 0.903 (95%CI: 0.815 - 0.965), and 0.861 (95%CI: 0.811 - 0.906) in the ACRIN 6698 training, ACRIN 6698 test and external test cohorts, respectively, which were significantly higher than those of the clinical model (AUC: 0.720 [95%CI: 0.587 - 0.842], 0.738 [95%CI: 0.669 - 0.796] for the two test cohorts, respectively; p < 0.05) and Pre-C (AUC: 0.697 [95%CI: 0.554 - 0.819], 0.726 [95%CI: 0.666 - 0.797] for the two test cohorts, respectively; p < 0.05). High AUCs of the MESN-C maintained in the ACRIN 6698 standard (AUC = 0.853 [95%CI: 0.676 - 1.000]) and experimental (AUC = 0.905 [95%CI: 0.817 - 0.993]) subcohorts, and the interracial and external subcohort (AUC = 0.861 [95%CI: 0.811 - 0.906]). Moreover, the MESN-C increased the positive predictive value from 48.6 to 71.3% compared with Pre-C model, and maintained a high negative predictive value (80.4-86.7%).</p><p><strong>Conclusion: </strong>The MESN-C using longitudinal multiparametric MRI after a short-term therapy achieved favorable performance for predicting pCR, which could facilitate timely adjustment of treatment regimens, increasing the rates of pCR and avoiding toxic effects.</p><p><strong>Trial registration: </strong>Trial registration at https://www.chictr.org.cn/ .</p><p><strong>Registration number: </strong>ChiCTR2000038578, registered September 24, 2020.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"52"},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypes and cytokines of NK cells in triple-negative breast cancer resistant to checkpoint blockade immunotherapy.","authors":"Youlong Wang, Yongluo Jiang, Fadian Ding, Jun Lu, Tong Huang, Guanqing Zhong, Pengfei Zhu, Yue Ma, Jin Li, Xinjia Wang, Jiacai Lin, Hongjun Zheng, Weidong Wang, Yiwei Xu, Xiajie Lyu, Yu Si Niu, Xin Qi, Jinjian Li, Bocen Chen, Tingting He, Jiling Zeng, Yifei Ma","doi":"10.1186/s13058-025-02003-y","DOIUrl":"10.1186/s13058-025-02003-y","url":null,"abstract":"<p><p>Neoadjuvant checkpoint blockade immunotherapy (NATI) significantly prolonged outcomes for triple-negative breast cancer (TNBC). Residual tumor cells that survive NATI represent high-risk cell populations with metastatic potential and usually evade immunosurveillance by NK cells. Using an 82-protein panel, we here profiled single-cell membrane proteomics of CD56+ (NCAM1+) NK cells from tumor, peri-cancerous tissue, as well as peripheral blood from 28 TNBC patients post-NATI of residual cancer burden II/III. Unsupervised clustering resulted in several distinct clusters: 2 tumor-infiltrating NK (TINK) clusters with divergent functions of immune activation (TNFRSF7+) and suppression (SELL+); 2 immuno-suppressive peri-cancerous clusters; and 1 periphery-specific cluster. Considering the contradiction of the 2 TINK clusters, we further tested cytokine functions of SELL + and TNFRSF7 + TINKs by single-cell secreting proteomics using a 32-cytokine panel. Consistently, SELL + TINK clusters were characterized by immuno-suppressive secretion patterns (IL10+). A low proportion of SELL + TINK cluster and low proportion of IL10 + secreting SELL + TINK cluster (single-cell secreting proteomics) were both associated with better progression-free survival time. These findings were validated in an independent cohort of 15 patients during 16-month follow-up. Overall, we identified a distinct immuno-suppressive TINK cell group, featuring IL10 + secreting and SELL expression with a strong relation to poor survival prognosis in TNBC patients post-NATI.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"51"},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of T cell subpopulations and plasma cytokines during the first year of antineoplastic therapy in patients with breast cancer: the BEGYN-1 study.","authors":"Elisabeth Kaiser, Regine Weber, Melanie Hirschstein, Hala Mazid, Emilie Marie Suzanne Kapps, Muriel Charlotte Hans, Michelle Bous, Sybelle Goedicke-Fritz, Gudrun Wagenpfeil, Michael Zemlin, Erich-Franz Solomayer, Carolin Müller, Cosima Zemlin","doi":"10.1186/s13058-025-01997-9","DOIUrl":"10.1186/s13058-025-01997-9","url":null,"abstract":"<p><strong>Background: </strong>The role of T cell immunity during antineoplastic therapy is poorly understood. In the BEGYN-1 study, patients with breast cancer underwent quarterly assessments prior to and during antineoplastic therapy over a period of 12 months.</p><p><strong>Methods: </strong>We used flow cytometry and multiplex immunoassays to quantify 25 T cell subpopulations and seven T cell associated plasma cytokines in peripheral blood from 92 non-metastatic breast cancer patients, respectively. In addition, the association between T cell dynamics and the outcome of patients undergoing neoadjuvant chemotherapy was investigated.</p><p><strong>Results: </strong>In patients undergoing chemotherapy, a significant reduction in T helper (Th) cells, particularly naïve central and effector cells and thymus positive Th cells, was observed over time. Interestingly, Th1 immune response-associated cytokines (IL-12, TNF, IFN-γ) declined while Th2 cells and cytotoxic T cells increased over time.</p><p><strong>Conclusions: </strong>We conclude that in breast cancer patients, chemotherapy is associated with a transition from a Th1 immune response towards Th2 and an increase in cytotoxic T cells, whereas in patients without chemotherapy, these alterations were less pronounced. Future studies should clarify whether patterns of T cell subsets or plasma cytokines can be used as biomarkers to monitor or even improve therapeutic interventions.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"50"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR screens with trastuzumab emtansine in HER2-positive breast cancer cell lines reveal new insights into drug resistance.","authors":"Barbara A Lipert, Kyla N Siemens, Aziza Khan, Rebecca Airey, Gech Heng Dam, Man Lu, Marcella Flinterman, Queenie Yong, Tet Woo Lee, Francis W Hunter, Stephen M F Jamieson","doi":"10.1186/s13058-025-02000-1","DOIUrl":"10.1186/s13058-025-02000-1","url":null,"abstract":"<p><strong>Background: </strong>Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is an effective therapy for HER2-positive breast cancer; however, its efficacy is limited by drug resistance. While multiple mechanisms of resistance have been proposed, these are not yet well understood. Greater understanding of T-DM1 sensitivity and resistance could provide new combination strategies to overcome resistance or predictive biomarkers to guide therapy.</p><p><strong>Methods: </strong>We have conducted CRISPR/Cas9 functional genomics modifier screens in HER2-positive breast cancer cell lines to allow for unbiased discovery of T-DM1 sensitivity and resistance genes. Whole-genome knockout screens were carried out in MDA-MB-361 and MDA-MB-453 cells treated with T-DM1 and its payload cytotoxin DM1. Hits were validated in secondary T-DM1 screens using a focused single-guide RNA (sgRNA) library and subsequently by individual gene knockout.</p><p><strong>Results: </strong>The whole-genome CRISPR screens with T-DM1 and DM1 identified 599 genes as potential modifiers of T-DM1 sensitivity and resistance. Of these, 17 genes were significantly enriched and 3 genes depleted at P < 0.001 in either or both MDA-MB-361 and MDA-MB-453 libraries in the secondary screens. Among the top hits, were known T-DM1 sensitivity genes ERBB2 and SLC46A3, in addition to negative regulators of mTOR complex 1: TSC1 and TSC2. MDA-MB-453 clones with knockout of TSC1 or partial knockout of TSC2 were more resistant to T-DM1 than wild type cells in competition growth assays and to T-DM1 and other HER2 targeting therapies (T-DXd, lapatinib and neratinib) in growth inhibition assays, and had increased internalisation of T-DM1 at 6 h. T-DM1 and the mTOR inhibitor everolimus demonstrated synergistic activity at inhibiting cell proliferation at multiple T-DM1 concentrations across four HER2-positive breast cancer cell lines.</p><p><strong>Conclusions: </strong>Our CRISPR screening approach with T-DM1 in HER2-positive breast cancer cell lines identified genes not previously implicated in T-DM1 sensitivity or resistance, including TSC1 and TSC2. These genes may inform new strategies to enhance T-DM1 therapy in the clinic.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"48"},"PeriodicalIF":7.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone acetylation modulators in breast cancer.","authors":"Xueying Yuan, Jeffrey M Rosen","doi":"10.1186/s13058-025-02006-9","DOIUrl":"10.1186/s13058-025-02006-9","url":null,"abstract":"<p><p>Breast cancer is the most prevalent cancer in women worldwide. Aberrant epigenetic reprogramming such as dysregulation of histone acetylation has been associated with the development of breast cancer. Histone acetylation modulators have been targeted as potential treatments for breast cancer. This review comprehensively discusses the roles of these modulators and the effects of their inhibitors on breast cancer. In addition, epigenetic reprogramming not only affects breast cancer cells but also the immunosuppressive myeloid cells, which can facilitate breast cancer progression. Therefore, the review also highlights the roles of these immunosuppressive myeloid cells and summarizes how histone acetylation modulators affect their functions and phenotypes. This review provides insights into histone acetylation modulators as potential therapeutic targets for breast cancer.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"49"},"PeriodicalIF":7.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}