Breast Cancer Research最新文献

{"title":"Prediction of pathological complete response after neoadjuvant chemotherapy for HER2-negative breast cancer patients with routine immunohistochemical markers.","authors":"Lothar Häberle, Ramona Erber, Paul Gass, Alexander Hein, Melitta Niklos, Bernhard Volz, Carolin C Hack, Rüdiger Schulz-Wendtland, Hanna Huebner, Chloë Goossens, Matthias Christgen, Thilo Dörk, Tjoung-Won Park-Simon, Andreas Schneeweiss, Michael Untch, Valentina Nekljudova, Sibylle Loibl, Arndt Hartmann, Matthias W Beckmann, Peter A Fasching","doi":"10.1186/s13058-025-01960-8","DOIUrl":"10.1186/s13058-025-01960-8","url":null,"abstract":"<p><strong>Background: </strong>Pathological complete response (pCR) is an established surrogate marker for prognosis in patients with breast cancer (BC) after neoadjuvant chemotherapy. Individualized pCR prediction based on clinical information available at biopsy, particularly immunohistochemical (IHC) markers, may help identify patients who could benefit from preoperative chemotherapy.</p><p><strong>Methods: </strong>Data from patients with HER2-negative BC who underwent neoadjuvant chemotherapy from 2002 to 2020 (n = 1166) were used to develop multivariable prediction models to estimate the probability of pCR (pCR-prob). The most precise model identified using cross-validation was implemented in an online calculator and a nomogram. Associations among pCR-prob, prognostic IHC3 distant recurrence and disease-free survival were studied using Cox regression and Kaplan-Meier analyses. The model's utility was further evaluated in independent external validation cohorts.</p><p><strong>Results: </strong>273 patients (23.4%) achieved a pCR. The most precise model had across-validated area under the curve (AUC) of 0.84, sensitivity of 0.82, and specificity of 0.71. External validation yielded AUCs between 0.75 (95% CI, 0.70-0.81) and 0.83 (95% CI, 0.78-0.87). The higher the pCR-prob, the greater the prognostic impact of pCR status (presence/absence): hazard ratios decreased from 0.55 (95% central range, 0.07-1.77) at 0% to 0.20 (0.11-0.31) at 50% pCR-prob. Combining pCR-prob and IHC3 score further improved the precision of disease-free survival prognosis.</p><p><strong>Conclusions: </strong>A pCR prediction model for neoadjuvant therapy decision-making was established. Combining pCR and recurrence prediction allows identification of not only patients who benefit most from neoadjuvant chemotherapy, but also patients with a very unfavorable prognosis for whom alternative treatment strategies should be considered.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"13"},"PeriodicalIF":7.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042993","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":"Natural killer cells occupy unique spatial neighborhoods in HER2^- and HER2⁺ human breast cancers.","authors":"Femke A I Ehlers, Katie E Blise, Courtney B Betts, Shamilene Sivagnanam, Loes F S Kooreman, E Shelley Hwang, Gerard M J Bos, Lotte Wieten, Lisa M Coussens","doi":"10.1186/s13058-025-01964-4","DOIUrl":"10.1186/s13058-025-01964-4","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocytes are considered clinically beneficial in breast cancer, but the significance of natural killer (NK) cells is less well characterized. As increasing evidence has demonstrated that the spatial organization of immune cells in tumor microenvironments is a significant parameter for impacting disease progression as well as therapeutic responses, an improved understanding of tumor-infiltrating NK cells and their location within tumor contextures is needed to improve the design of effective NK cell-based therapies. In this study, we developed a multiplex immunohistochemistry (mIHC) antibody panel designed to quantitatively interrogate leukocyte lineages, focusing on NK cells and their phenotypes, in two independent breast cancer patient cohorts (n = 26 and n = 30). Owing to the clinical evidence supporting a significant role for NK cells in HER2⁺ breast cancer in mediating responses to Trastuzumab, we further evaluated HER2^- and HER2⁺ specimens separately. Consistent with literature, we found that CD3⁺ T cells were the dominant leukocyte subset across breast cancer specimens. In comparison, NK cells, identified by CD56 or NKp46 expression, were scarce in all specimens with low granzyme B expression indicating reduced cytotoxic functionality. Whereas NK cell density and phenotype did not appear to be influenced by HER2 status, spatial analysis revealed distinct NK cells phenotypes regarding their proximity to neoplastic tumor cells that associated with HER2 status. Spatial cellular neighborhood analysis revealed multiple unique neighborhood compositions surrounding NK cells, where NK cells from HER2^- tumors were more frequently found proximal to neoplastic tumor cells, whereas NK cells from HER2⁺ tumors were instead more frequently found proximal to CD3⁺ T cells. This study establishes the utility of quantitative mIHC to evaluate NK cells at the single-cell spatial proteomics level and illustrates how spatial characteristics of NK cell neighborhoods vary within the context of HER2^- and HER2⁺ breast cancers.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"14"},"PeriodicalIF":7.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042990","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":"Outcomes in stage IIA versus stage IIB/III in the PALLAS trial [ABCSG-42/AFT-05/PrE0109/BIG-14-13]).","authors":"A DeMichele, A C Dueck, D Hlauschek, M Martin, H Burstein, G Pfeiler, N Zdenkowski, A Wolff, M Bellet-Ezquerra, E Winer, M Balic, K Miller, M Colleoni, D Lake, G Rubovsky, D Cameron, J Balko, C F Singer, Z Nowecki, H Iwata, N Wolmark, K A Parraga, H Rugo, G G Steger, T Traina, G Werutsky, D Czajkowska, O Metzger, S El-Abed, K P Theall, R D Lu, P O'Brien, C Fesl, E Mayer, M Gnant","doi":"10.1186/s13058-024-01941-3","DOIUrl":"10.1186/s13058-024-01941-3","url":null,"abstract":"<p><strong>Background: </strong>The PALLAS trial investigated the addition of palbociclib to standard adjuvant endocrine therapy to reduce breast cancer recurrence. This pre-specified analysis was conducted to determine whether adjuvant palbociclib benefited patients diagnosed with lower risk stage IIA disease compared to those with higher stage disease.</p><p><strong>Methods: </strong>PALLAS was an international, multicenter, randomized, open-label, phase III trial, representing a public-private partnership between Pfizer, the Austrian Breast Cancer Study Group, and the U.S. ALLIANCE Foundation. Patients diagnosed with stage II-III, hormone-receptor-positive, HER2/neu negative breast cancer within 12 months of diagnosis had completed all definitive therapy aside from endocrine therapy (started within 6 months prior to study entry) were eligible. All patients were required to submit a formalin-fixed paraffin-embedded (FFPE) tumor block. Patients were randomly assigned 1:1 to receive standard adjuvant endocrine therapy (of physicians' choice) for at least 5 years with or without 2 years of palbociclib, administered orally at a starting dose of 125 mg daily, given for 21 days followed by a 7-day break.</p><p><strong>Results: </strong>A total of 5,796 patients with HR + /HER2- early breast cancer (including 1,010 with stage IIA) were enrolled. Median follow-up was 50 months for stage IIA patients and 43.1 months overall. In the stage IIA cohort, 4-year iDFS in the palbociclib arm was 92.9% versus 92.1% for ET alone (HR 0.75, 95%CI 0.48-1.19, p = 0.23). There was no differential benefit by histologic grade, chemotherapy receipt, age, or anatomic/clinical risk. Additionally, no benefit to palbociclib was seen in this cohort in invasive breast cancer-free survival (iBCFS), locoregional relapse-free survival (LRFS), distant relapse-free survival (DRFS), or overall survival (OS). For the stage IIB/III patients, 4-year iDFS was 85.3% for palbociclib + ET versus 83.6% for ET alone (HR 0.91, 95% CI 0.77-1.07, p = 0.24).</p><p><strong>Conclusions and relevance: </strong>While there were substantial differences in outcome for stage IIA versus IIB/III patients at 4 years of follow-up, the addition of 2 years of palbociclib did not improve outcomes for patients, regardless of stage.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov number NCT02513394 Registered 30 Jul 2015.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"12"},"PeriodicalIF":7.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029626","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":"Obesity increases DNA damage in the breast epithelium.","authors":"Mohamed Gaber, Arnaud Quentel, Julia Holmes, Cassandra Lepetit, Hana Triki, Adam Wilson, Valerie Payne, Iliana Tenvooren, Cloé Dehours, Abigail Peoples, Mary L Duet, Adam J Katz, Thierry Pécot, Gwenola Bougras-Cartron, Pierre-François Cartron, Katherine L Cook, Pierre-Alexandre Vidi","doi":"10.1186/s13058-025-01961-7","DOIUrl":"10.1186/s13058-025-01961-7","url":null,"abstract":"<p><p>Obesity is a modifiable risk factor for breast cancer. Yet, how obesity contributes to cancer initiation is not fully understood. The goal of this study was to determine if the body mass index (BMI) and metabolic hallmarks of obesity are related to DNA damage in normal breast tissue. In a mouse model of diet-induced obesity, weight gain was associated with elevated levels of DNA double-strand breaks in the mammary gland. We also found a positive correlation between BMI and DNA breaks in the breast epithelium of premenopausal women (but not postmenopausal women). High BMI was associated with elevated systemic and tissue-level oxidative DNA damage across the lifespan, and we propose that the breast epithelium undergoing menstruous proliferation waves is particularly prone to the generation of DNA breaks from oxidative lesions. Ancestry was an important modulator of the obesity-DNA break connection. Compared to non-Hispanic Whites, women identifying as African Americans had higher levels of DNA breaks, as well as elevated leptin and IGF-1. In 3D cultures of breast acini, both leptin and IGF-1 caused an accumulation of DNA damage. The results highlight a connection between premalignant genomic alterations in the breast epithelium and metabolic health modulated by obesity and ancestry. They call for attention on biological determinants of breast cancer risk disparities.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"11"},"PeriodicalIF":7.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014756","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":"Tumour DNA methylation markers associated with breast cancer survival: a replication study.","authors":"Elaheh Zarean, Shuai Li, Ee Ming Wong, Enes Makalic, Roger L Milne, Graham G Giles, Catriona McLean, Melissa C Southey, Pierre-Antoine Dugué","doi":"10.1186/s13058-024-01955-x","DOIUrl":"10.1186/s13058-024-01955-x","url":null,"abstract":"<p><strong>Background: </strong>Tumour DNA methylation has been investigated as a potential marker for breast cancer survival, but findings often lack replication across studies.</p><p><strong>Methods: </strong>This study sought to replicate previously reported associations for individual CpG sites and multi-CpG signatures using an Australian sample of 425 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS). Candidate methylation sites (N = 22) and signatures (N = 3) potentially associated with breast cancer survival were identified from five prior studies that used The Cancer Genome Atlas (TCGA) methylation dataset, which shares key characteristics with the MCCS: comparable sample size, tissue type (formalin-fixed paraffin-embedded; FFPE), technology (Illumina HumanMethylation450 array), and participant characteristics (age, ancestry, and disease subtype and severity). Cox proportional hazard regression analyses were conducted to assess associations between these markers and both breast cancer-specific survival and overall survival, adjusting for relevant participant characteristics.</p><p><strong>Results: </strong>Our findings revealed partial replication for both individual CpG sites (9 out of 22) and multi-CpG signatures (2 out of 3). These associations were maintained after adjustment for participant characteristics and were stronger for breast cancer-specific mortality than for overall mortality. In fully-adjusted models, strong associations were observed for a CpG in PRAC2 (per standard deviation [SD], HR = 1.67, 95%CI: 1.24-2.25) and a signature based on 28 CpGs developed using elastic net (per SD, HR = 1.48, 95%CI: 1.09-2.00).</p><p><strong>Conclusions: </strong>While further studies are needed to confirm and expand on these findings, our study suggests that DNA methylation markers hold promise for improving breast cancer prognostication.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"9"},"PeriodicalIF":7.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014760","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":"Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells.","authors":"K S Young, G R Hancock, E C Fink, A Zigrossi, B Flowers, D A Cooper, V T Nguyen, M C Martinez, K S Mon, M Bosland, D R Zak, A P Runde, M N Sharifi, I Kastrati, D D L Minh, S Kregel, Sean W Fanning","doi":"10.1186/s13058-024-01945-z","DOIUrl":"10.1186/s13058-024-01945-z","url":null,"abstract":"<p><p>Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER + breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER + breast cancers.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"10"},"PeriodicalIF":7.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014758","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":"Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors.","authors":"Romain Pacaud, Scott Thomas, Sibapriya Chaudhuri, Ann Lazar, Luika A Timmerman, Pamela N Munster","doi":"10.1186/s13058-024-01954-y","DOIUrl":"10.1186/s13058-024-01954-y","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-Ribose) polymerase inhibitors are approved for treatment of tumors with BRCA1/2 and other homologous recombination repair (HRR) mutations. However, clinical responses are often not durable and treatment may be detrimental in advanced cancer due to excessive toxicities. Thus we are seeking alternative therapeutics to enhance PARP-directed outcomes. In an effort to expand the clinical use of PARP inhibitors to HRR proficient tumors, several groups have tested combinations of DNA methyltransferase inhibitors and PARP inhibitors. While this approach attenuated tumor cell proliferation in preclinical studies, subsequent clinical trials revealed little benefit. We hypothesized that benefit for this drug combination would only be specific to HRR deficient tumors, due to their inability to enact high fidelity DNA repair with subsequent cell death.</p><p><strong>Methods: </strong>We generated hypomorphic BRCA1 and BRCA2 variants of the HRR proficient triple negative breast cancer cell line MDA-MB-231. We compared therapeutic response features such as RAD51 focus formation, cell cycle fraction alterations, DNA damage accumulation, colony formation, and cell death of these and other cell lines with and without intrinsic BRCA1/2 mutations. Results were confirmed in BRCA1/2 intact and deficient xenografts and PDX.</p><p><strong>Results: </strong>Our targeted variants and cells with intrinsic BRCA1/2 mutations responded to low dose combination therapeutic treatment by G2M stalling, compounded DNA damage, severely attenuated colony formation, and importantly, increased cell death. In contrast, the parental MDA-MB-231 cells and other HRR proficient cell lines produced smaller cell populations with short term treatment, but with much less cumulative DNA damage, and minimal cell death. In animal studies, our BRCA-engineered hypomorphs and several independent PDX models with clinically relevant BRCA mutations were acutely more vulnerable to this drug combination.</p><p><strong>Conclusions: </strong>We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"8"},"PeriodicalIF":7.4,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014788","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":"Los olvidados: Non-BRCA variants associated with Hereditary breast cancer in Mexican population.","authors":"Dione Aguilar, María Lourdes Garza-Rodríguez, Carolina Elizabeth Muñiz-Garza, Fernando Alcorta Nuñez, Cynthia Mayte Villarreal-Garza, Oscar Vidal-Gutiérrez, Diana Cristina Pérez-Ibave, Carlos Horacio Burciaga-Flores","doi":"10.1186/s13058-024-01957-9","DOIUrl":"https://doi.org/10.1186/s13058-024-01957-9","url":null,"abstract":"<p><strong>Background: </strong>Hereditary predisposition to breast and ovarian cancer syndrome (HBOC) is a pathological condition with increased cancer risk, including breast (BC), ovarian cancer (OC), and others. HBOC pathogenesis is caused mainly by germline pathogenic variants (GPV) in BRCA1 and BRCA2 genes. However, other relevant genes are related to this syndrome diagnosis, prognosis, and treatment, including TP53, PALB2, CHEK2, ATM, etc. This study aimed to identify the prevalence of non-BRCA genes in HBOC patients of Northeast Mexico.</p><p><strong>Methods: </strong>This multicentric study included 1285 patients with HBOC diagnosis from four oncologic centers in northeast Mexico from 2016 to 2023. Genomic and clinical data were analyzed based on multi-gene panel results and electronic records of the medical geneticist consultation. For the data analysis of qualitative and quantitative variants, JASP statistical software (version 0.18.1) was used, taking p < 0.05 as a significant result.</p><p><strong>Results: </strong>We found that 32.7% of the patients had at least one GPV in non-BRCA genes. The five most frequent non-BRCA genes were CHEK2, PALB2, MUTYH, CDKN2A, and ATM. Among the group of non-BRCA genes, six are involved in the homologous repair pathway (HR), and three are related to DNA damage repair (DDR) pathways. In analyzing GPVs in molecular pathways, both have similar frequencies with no statistical difference for BC.</p><p><strong>Conclusion: </strong>Multi-gene testing implementation improves the detection of often overlooked genes related to HBOC pathogenesis and treatment. Non-BRCA GPVs in Northern Mexico correspond to one-third of the HBOC cases, including HR and DDR pathways genes that would be misdiagnosed if not tested. HR patient carriers are potential targets of iPARP therapies. The optimal approach to cancer treatment for non-BRCA mutation carriers warrants further investigation to develop newer therapies.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"7"},"PeriodicalIF":7.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056142","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":"Annotation-free deep learning algorithm trained on hematoxylin & eosin images predicts epithelial-to-mesenchymal transition phenotype and endocrine response in estrogen receptor-positive breast cancer.","authors":"Kaimin Hu, Yinan Wu, Yajing Huang, Meiqi Zhou, Yanyan Wang, Xingru Huang","doi":"10.1186/s13058-025-01959-1","DOIUrl":"10.1186/s13058-025-01959-1","url":null,"abstract":"<p><p>Recent evidence indicates that endocrine resistance in estrogen receptor-positive (ER+) breast cancer is closely correlated with phenotypic characteristics of epithelial-to-mesenchymal transition (EMT). Nonetheless, identifying tumor tissues with a mesenchymal phenotype remains challenging in clinical practice. In this study, we validated the correlation between EMT status and resistance to endocrine therapy in ER+ breast cancer from a transcriptomic perspective. To confirm the presence of morphological discrepancies in tumor tissues of ER+ breast cancer classified as epithelial- and mesenchymal-phenotypes according to EMT-related transcriptional features, we trained deep learning algorithms based on EfficientNetV2 architecture to assign the phenotypic status for each patient utilizing hematoxylin & eosin (H&E)-stained slides from The Cancer Genome Atlas database. Our classifier model accurately identified the precise phenotypic status, achieving an area under the curve (AUC) of 0.886 at the tile-level and an AUC of 0.910 at the slide-level. Furthermore, we evaluated the efficacy of the classifier in predicting endocrine response using data from an independent ER+ breast cancer patient cohort. Our classifier achieved a predicting accuracy of 81.25%, and 88.7% slides labeled as endocrine resistant were predicted as the mesenchymal-phenotype, while 75.6% slides labeled as sensitive were predicted as the epithelial-phenotype. Our work introduces an H&E-based framework capable of accurately predicting EMT phenotype and endocrine response for ER+ breast cancer, demonstrating its potential for clinical application and benefit.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"6"},"PeriodicalIF":7.4,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972982","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":"Secreted LGALS3BP facilitates distant metastasis of breast cancer.","authors":"Seung-Su Kim, Issac Park, Jeesoo Kim, Na-Lee Ka, Ga Young Lim, Mi-Ye Park, Sewon Hwang, Ji-Eun Kim, So Yeon Park, Jong-Seo Kim, Hyun-Woo Rhee, Mi-Ock Lee","doi":"10.1186/s13058-024-01958-8","DOIUrl":"https://doi.org/10.1186/s13058-024-01958-8","url":null,"abstract":"<p><strong>Background: </strong>Patients with estrogen receptor (ER)-positive breast cancer (BC) can be treated with endocrine therapy targeting ER, however, metastatic recurrence occurs in 25% of the patients who have initially been treated. Secreted proteins from tumors play important roles in cancer metastasis but previous methods for isolating secretory proteins had limitations in identifying novel targets.</p><p><strong>Methods: </strong>We applied an in situ secretory protein labeling technique using TurboID to analyze secretome from tamoxifen-resistant (TAMR) BC. The increased expression of LGALS3BP was validated using western blotting, qPCR, ELISA, and IF. Chromatin immunoprecipitation was applied to analyze estrogen-dependent regulation of LGALS3BP transcription. The adhesive and angiogenic functions of LGALS3BP were evaluated by abrogating LGALS3BP expression using either shRNA-mediated knockdown or a neutralizing antibody. Xenograft mouse experiments were employed to assess the in vivo metastatic potential of TAMR cells and the LGALS3BP protein. Clinical evaluation of LGALS3BP risk was carried out with refractory clinical specimens from tamoxifen-treated ER-positive BC patients and publicly available databases.</p><p><strong>Results: </strong>TAMR secretome analysis revealed that 176 proteins were secreted at least 2-fold more from MCF7/TAMR cells than from sensitive cells, and biological processes such as cell adhesion and angiogenesis were associated with the TAMR secretome. Galectin-3 binding protein (LGALS3BP) was one of the top 10 most highly secreted proteins in the TAMR secretome. The expression level of LGALS3BP was suppressed by estrogen signaling, which involves direct ERα binding to its promoter region. Secreted LGALS3BP in the TAMR secretome helped BC cells adhere to the extracellular matrix and promoted the tube formation of human umbilical vein endothelial cells. Compared with sensitive cells, xenograft animal experiments with MCF7/TAMR cells showed increased pulmonary metastasis, which completely disappeared in LGALS3BP-knockdown TAMR cells. Finally, higher levels of LGALS3BP were associated with poor prognosis in ER-positive BC patients treated with adjuvant tamoxifen in the clinic.</p><p><strong>Conclusion: </strong>TAMR secretome analysis identified secretory proteins, such as LGALS3BP, that are involved in biological processes closely related to metastasis. Secreted LGALS3BP from the TAMR cells promoted adhesion of the cells to the extracellular matrix and vasculature formation, which may support metastasis of TAMR cells.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"4"},"PeriodicalIF":7.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11715970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056117","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}