Breast Cancer Research最新文献

{"title":"High-fat diet reshapes microbial interactions to promote breast cancer stemness via Streptococcus mutans-induced leucine accumulation.","authors":"Chao Cheng, Fahu Yuan, Jincheng Li, Yixian Fan, Yang Liu, Quan Zhang, Yanjun Lu, Lei He","doi":"10.1186/s13058-026-02297-6","DOIUrl":"https://doi.org/10.1186/s13058-026-02297-6","url":null,"abstract":"<p><strong>Background: </strong>Obesity and high-fat diet (HFD) are established risk factors for breast cancer, but the mechanisms by which dietary-induced gut microbiota alterations influence cancer progression are not fully understood. The interplay between microbial composition, metabolites, and cancer progression warrants further exploration.</p><p><strong>Methods: </strong>We employed Mendelian randomization (MR) and Bayesian colocalization analyses based on genome-wide association studies (GWAS) to identify gut microbial genera causally linked to breast cancer risk. Multi-omics, including 16S rRNA sequencing, fecal metabolomics and RNA-seq, were performed to depict HFD-induced microbial and metabolic shifts in breast cancer-bearing mice. In vitro co-culture systems and in vivo murine models examined interactions between Roseburia intestinalis (R. intestinalis) and Streptococcus mutans (S. mutans) under HFD conditions. Functional assays, including immunofluorescence, qRT-PCR, probe-based assays and fluorescent in situ hybridization, and flow cytometry, evaluated cancer stemness, bacterial colonization, and the impact of leucine metabolism.</p><p><strong>Results: </strong>MR analysis revealed Roseburia as a potential causal microbial risk factor for breast cancer, with colocalized genes enriched in fatty acid metabolism. HFD feeding promoted the co-occurrence of R. intestinalis and S. mutans, facilitating S. mutans intratumoral colonization and consequent leucine accumulation in the tumor microenvironment (TME). S. mutans-derived leucine robustly enhanced breast cancer cell proliferation and stemness, as evidenced by increased tumor sphere formation and upregulation of CD44, CD133, and SOX2. Functional blockade of leucine transport with BCH attenuated S. mutans-mediated tumor growth and limited tumor-associated macrophage activation in vivo.</p><p><strong>Conclusions: </strong>This study reveals that HFD-induced reshaping of microbial interactions, particularly a commensal-like interaction between S. mutans and R. intestinalis, is associated with leucine accumulation in the TME, thereby supporting breast cancer stemness and progression. Targeting S. mutans-mediated leucine accumulation represents a promising strategy for therapeutic intervention in obesity-related breast cancer. Our findings highlight the pivotal role of dietary-microbiota crosstalk in modulating the TME and cancer stemness.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor ecology and the paradox of clean margins in multicentric breast cancer: an exploratory organoid-based functional study.","authors":"Nuria G Martínez-Illescas, Estrella Martín-Zapater, Camila Quezada-Gutiérrez, Laura Yébenes, Ana Payo-Payo, Laura Frías-Aldeguer, María Salazar-Roa","doi":"10.1186/s13058-026-02301-z","DOIUrl":"https://doi.org/10.1186/s13058-026-02301-z","url":null,"abstract":"<p><p>The gene-centric view of cancer has provided important mechanistic insights, but does not fully account for the clinical heterogeneity observed in complex cases. An eco-evolutionary framework instead conceptualizes tumors as dynamic systems shaped by interactions among malignant clones, stromal components, immune populations and the surrounding microenvironment. Multicentric/multifocal breast cancer (MMBC) provides a relevant context in which to explore this biological complexity. Using patient-derived organoids, we observed that organoids derived from histologically tumor-free margins can display stem-like and basal-like features under defined culture conditions, whereas those from primary tumor regions may exhibit more differentiated phenotypes. These observations suggest that histological margin status alone may not fully capture the functional heterogeneity of peritumoral tissue. Our findings support the hypothesis that biological influences within the margin region may contribute to shaping cellular phenotypes beyond the presence of overt malignant cells. Overall, this study highlights the potential value of integrating organoid-based functional approaches with eco-evolutionary concepts to further investigate the biological landscape of the peritumoral field in MMBC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging immune and clinicopathological profiles with machine learning to predict axillary lymph node metastasis in breast cancer patients.","authors":"Alba Fischer-Carles, Alessio Fiorin, Carlos López Pablo, Laia Reverté, Esther Sauras-Colón, Noèlia Gallardo-Borràs, Marylène Lejeune, Mikel Relloso Ortiz de Uriarte, Tábata Sánchez-Alcántara, Maria Ballester-Navarro, Ramon Bosch Príncep, Laia Adalid-Llansa, Elena Goyda, Daniel Mata Cano, Jérôme Noailly, Gemma Piella","doi":"10.1186/s13058-026-02294-9","DOIUrl":"https://doi.org/10.1186/s13058-026-02294-9","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the leading cause of cancer-related death in women, with mortality increasing when tumor cells spread to nearby lymph nodes, particularly the axillary lymph nodes (ALNs). Although several studies predict patients with ALN metastasis at diagnosis (pdALN⁺), few examine the prognostic value of immune elements within ALNs. Given the impact of immune response on breast cancer, this study develops a machine learning model to identify the clinicopathological and immune features of the primary tumor and non-metastatic ALNs (ALN^-) most frequently associated with pdALN⁺.</p><p><strong>Methods: </strong>Two datasets of luminal breast cancer patients diagnosed between 1995 and 2008 were used: Dataset 1 involved 83 women (42 pdALN^- and 41 pdALN⁺), and Dataset 2 comprised 344 women (204 pdALN^- and 140 pdALN⁺). Three machine learning models were developed using the Random Forest algorithm: Model 1 included clinicopathological data from Dataset 1; Model 2 used clinicopathological and immune response data from Dataset 1; and Model 3 used clinicopathological data from Dataset 2. All models followed the same machine learning pipeline, including data pre-processing, feature selection using recursive feature elimination with cross-validation, algorithm optimization using random search cross-validation, and results interpretability using Shapley additive explanations values. After selecting the best-performing model, Model 4 was developed using its dataset and features. The optimal feature set was determined at the point where adding more features led to a decline in model performance metrics.</p><p><strong>Results: </strong>Model 2 outperformed Models 1 and 3, despite the larger cohort on which Model 3 was developed. This highlights the crucial role of the immune response in breast cancer progression. Model 4 achieved a median ROC AUC of 0.84, a median accuracy of 0.76, and a median recall of 0.75. Remarkably, nine of the ten predictive features were immune populations. The intratumoral follicular dendritic cell marker CD21⁺ was the most predictive feature, even surpassing tumor diameter, a well-established prognostic factor in breast cancer. Thus, it might stand as a novel biomarker candidate.</p><p><strong>Conclusions: </strong>This study not only identifies promising biomarker candidates but also highlights the importance of including mechanistic features, such as mediating inflammation, in breast cancer patient stratification.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of primary tumor growth and metastasis in models of triple-negative breast cancer following tilorone administration via type I interferon signaling.","authors":"Alastair A E Saunders, Kellie A Mouchemore, Laura Vojtech, Lauren S James, Thomas B Chadwick, Lap Hing Chi, Chris Karagiannis, Caroline Bell, Rachel E Thomson, Belinda S Parker, Robin L Anderson, Paul Gregorevic","doi":"10.1186/s13058-026-02296-7","DOIUrl":"https://doi.org/10.1186/s13058-026-02296-7","url":null,"abstract":"<p><strong>Background: </strong>People with triple-negative breast cancer (TNBC) typically have poorer survival than those with other breast cancer subtypes, with fewer treatment options available. Type I interferon (IFN) signaling has been reported as an important regulator of metastasis and therapeutic response in TNBC, but the off-target toxicity of IFN therapies has limited progression to clinical use. Augmenting Bone Morphogenetic Protein (BMP) signaling has also been associated with anti-metastatic effects, but BMP therapies are not clinically available presently. Tilorone is an anti-viral drug that induces IFN signaling, which has recently gained added attention as an enhancer of BMP signaling. As an agent capable of enhancing two mechanisms of interest, we therefore aimed to test the therapeutic effects of tilorone in preclinical models of metastatic breast cancer.</p><p><strong>Methods: </strong>The effect of tilorone on 4T1.2, EMT6.5, TBCP-1 and MDA-MB-231-HM cells was studied using multiple in vitro assays. We also compared metastatic burden by qPCR in mice bearing orthotopic 4T1.2 mammary tumors - a syngeneic and metastatic model of TNBC - with and without tilorone by unpaired t-tests. The effect of tilorone in combination with 4 mg/kg doxorubicin was tested by a 2-way ANOVA.</p><p><strong>Results: </strong>In 4T1.2 cells, tilorone increased expression of IFN stimulated genes (ISGs). Tilorone also reduced lung metastatic burden. Improvements in survival associated with tilorone administration were blunted in mice that lacked the IFNα/β receptor (IFNAR1). The anti-metastatic impact of tilorone was further examined in combination with doxorubicin. In mice bearing 4T1.2 tumors, and receiving doxorubicin, co-treatment with tilorone increased natural killer (NK) cell maturation in the primary tumor, increased CD4⁺ & CD8⁺ T cell activation and NK cell maturation in the pre-metastatic lung, and enhanced metastasis-free survival. Analysis of patient data identified high ISG gene expression in tumors correlated with increased overall survival in TNBC but not in patients with other breast cancer subtypes. Additionally, most ISGs were more highly expressed in the tumors of TNBC patients who responded to chemotherapy, compared to non-responders.</p><p><strong>Conclusions: </strong>Collectively, the data support the utility of tilorone and other inducers of IFN signaling to enhance the effects of chemotherapeutic drugs for treating metastatic breast cancers.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal radiomics incorporating intratumoral heterogeneity for prognostic assessment of metastatic outcomes in invasive breast cancer.","authors":"Liwei Sun, Zhengtong Wang, Weizhi Zhang, Yunfei Yang, Pei Nie, Wenjian Xu","doi":"10.1186/s13058-026-02287-8","DOIUrl":"https://doi.org/10.1186/s13058-026-02287-8","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to develop prognostic models of distant metastasis (DM) and bone metastasis (BM) in invasive breast cancer (IBC) incorporating whole-tumor radiomics, intratumoral heterogeneity (ITH) metrics.</p><p><strong>Methods: </strong>A total of 1097 patients with IBC from three centers were included and divided into a training cohort (n = 610), a validation cohort (n = 153), and two independent testing cohorts (n = 170 and n = 164). Whole-tumor radiomic features were extracted from two-dimensional regions of interest (ROIs) on mammography and three-dimensional ROIs on the second post-contrast phase of dynamic contrast-enhanced MRI, while ITH metrics were derived from enhancement-based subregions. Predictive performance was assessed for each model, and the resulting risk scores were further used for risk stratification analyses. SHapley Additive exPlanations (SHAP) were used to assess the importance of individual ITH metrics and to quantify the contributions of each component within the combined model.</p><p><strong>Results: </strong>The combined model achieved the highest concordance index and robust risk stratification performance for both DM and BM. SHAP analysis indicated that the radiomics-based risk score ranked as the most influential predictor across both endpoints, while the ITH score consistently showed higher relative importance for BM than for DM. Distance-, shape-, and topology-related ITH metrics were among the most influential contributors across both endpoints.</p><p><strong>Conclusion: </strong>The combined model demonstrated robust prognostic performance, and the differential contribution of the ITH score between DM and BM indicates a more prominent role of imaging-derived heterogeneity in BM.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ARTEMIS trial identifies immune activation as a key predictor of neoadjuvant chemotherapy response in triple-negative breast cancer.","authors":"Sahil Seth, Clinton Yam, Lei Huo, Bora Lim, Amanda L Rinkenbaugh, Jason B White, Elizabeth E Ravenberg, Xingzhi Song, Jennifer K Litton, Debu Tripathy, Vicente Valero, Senthil Damodaran, Banu Arun, Naoto T Ueno, Anthony Lucci, Alastair M Thompson, Elizabeth A Mittendorf, Gaiane M Rauch, Beatriz Adrada, Rosalind P Candelaria, Qingqing Ding, Reid T Powell, Nour K Abuhadra, Jianhua Zhang, Andrew Futreal, Giulio F Draetta, Helen Piwnica-Worms, William F Symmans, Jeffrey T Chang, Stacy L Moulder","doi":"10.1186/s13058-026-02290-z","DOIUrl":"https://doi.org/10.1186/s13058-026-02290-z","url":null,"abstract":"<p><strong>Background: </strong>Selecting treatments for triple-negative breast cancer (TNBC) remains challenging due to its high molecular and phenotypic heterogeneity. To maximize response rates, nearly all patients are treated with an aggressive combination of chemo-immunotherapy. However, since half of patients respond to chemotherapy alone and about a third do not respond at all, the majority of patients would benefit from alternative regimens. Thus, there is a pressing need to better personalize or de-escalate therapy using response-based biomarkers.</p><p><strong>Methods: </strong>To address this need, we conducted the ARTEMIS randomized trial (NCT02276443) to test whether a molecular classifier could predict response to treatment with neoadjuvant chemotherapy alone in early-stage TNBC, and to understand the correlates of response.</p><p><strong>Results: </strong>This study found that integrating a molecular classifier did not result in a statistically significant improvement in responses to doxorubicin and cyclophosphamide (AC), which increased from 33% pCR to 41% (p = 0.43). To identify more robust correlates of response, we found that the strongest predictors were related to the immune system. Using immune cell markers, tumors could be categorized into three subtypes linked to chemoresponse, \"immune hot sensitive,\" \"immune hot resistant,\" and \"immune cold.\" Notably, 50% of the immune hot tumors exhibited a pathological complete response, compared to only 8% of the immune cold tumors. The immune cold tumors represented a group of TNBC tumors characterized by chemoresistance, a mesenchymal phenotype, and signatures of FGF and TGF-β signaling, suggesting potential therapeutic strategies. Among the immune hot tumors, the sensitive subtype showed a stronger immune response and distinct spatial organization between cancer and immune cells compared to the resistant subtype despite their largely similar gene expression profiles.</p><p><strong>Conclusions: </strong>These data indicate that the immune contexture is a critical factor in the response to AC chemotherapy and provides a framework for selecting more effective and less toxic therapies for patients with TNBC.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov ID NCT02276443 2014-10-24.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome predictors of second breast events in ductal carcinoma in situ: a case‒control study including Black and White women.","authors":"Aditi Hazra, Emma Berdan, Thomas Walsh, Sarah Humble, Jen Tappenden, Katherine DeSchryver, Deborah Veis, Kiran Vij, Shannan Ho Sui, Graham A Colditz","doi":"10.1186/s13058-026-02257-0","DOIUrl":"https://doi.org/10.1186/s13058-026-02257-0","url":null,"abstract":"<p><strong>Background: </strong>Black women diagnosed with ductal carcinoma in situ (DCIS) experience disproportionately higher risk of second breast cancer events (SBEs), including both ipsilateral and contralateral recurrences, yet remain underrepresented in molecular biomarker studies compared to non-Hispanic White women.</p><p><strong>Methods: </strong>We performed RNA sequencing on 200 archival DCIS samples from the Resource of Archival Breast Tissue cohort, including 33% self-reported Black women. We correlated transcriptomic and clinical data to identify predictors of SBEs. Cases (n = 100) who developed SBEs between 1999 and 2019 were matched 1:1 to controls (n = 100) on age, race, and margin status, who remained event-free during a comparable follow-up period in this observational study. RNA-seq was conducted using the Illumina NovaSeq 6000 platform, which yielded high-quality transcriptomic profiles (13,460 protein-coding genes) from 141 out of 200 samples. Differential gene expression and pathway analyses were used to identify molecular predictors of SBE risk.</p><p><strong>Results: </strong>Principal component analysis demonstrated that transcriptomic variance was associated with race and follow-up duration. Four genes, CHGB, RBM20, SYP, and SYNJ2BP, were significantly associated with ipsilateral SBEs (FDR P value < 0.05). Interferon-alpha signaling was the most significantly enriched pathway in DCIS cases compared with controls. Gene signatures varied by recurrence site (e.g., contralateral SBEs) and covariates, including self-reported race. Our findings demonstrate the feasibility and value of RNA-seq from diverse archival DCIS specimens.</p><p><strong>Conclusion: </strong>We identified novel transcriptomic alterations associated with second breast cancer events in DCIS. Our results support the inclusion of racially diverse biospecimens in biomarker discovery. These findings warrant validation in independent cohorts. These molecular insights have the potential to refine risk prediction tools and inform equitable strategies for DCIS management.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiome modulates breast cancer risk in socially isolated mice.","authors":"Fabia de Oliveira Andrade, Christopher Staley, Lu Jin, Melike Ozgul-Onal, Maddie McDermott, Sercan Kenanoglu, Karla Andrade de Oliveira, Vivek Verma, Leena Hilakivi-Clarke","doi":"10.1186/s13058-026-02292-x","DOIUrl":"https://doi.org/10.1186/s13058-026-02292-x","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer risk and mortality are associated with disrupted gut microbiome functions which in turn can affect tumor immune responses. One source of disruption could be stress. Social isolation (SI) stress consistently increases breast cancer risk and mortality in preclinical models and women, but whether SI promotes mammary tumor growth by affecting gut microbiome has not been studied.</p><p><strong>Methods: </strong>We investigated if increased E0771 mammary tumorigenesis in SI female C57BL/6 mice was associated with changes in their gut microbiome by treating mice with an antibiotic mix that suppresses bacterial abundance and by performing fecal microbiota transplantation (FMT) from SI or group-housed (GH) donors to GH host. The effect of SI on anti-tumor CD8 + T and immunosuppressive Foxp3 + Treg cells was also studied.</p><p><strong>Results: </strong>Fecal bacteria that were present at different abundances between GH and SI mice were short chain fatty acid (SCFA) producers, and the most consistent change across three replicate studies was decreased fecal abundance of Akkermansia genus in SI mice. In addition, fecal propionic acid levels were reduced in SI mice, compared with GH mice, in agreement with Akkermansia being propionic acid producer. SI reduced the activation of CD8 + T cells systemically and in the tumor microenvironment, while the levels and activation of immunosuppressive Foxp3 Tregs were increased. Antibiotic treatment reversed increased mammary tumorigenesis and immunosuppression in SI mice but did not affect GH mice. Further, FMT from SI donors increased tumor growth in GH host, compared with FMT from GH donor.</p><p><strong>Conclusion: </strong>Gut dysbiosis caused by SI may be driving their increased mammary tumorigenesis, potentially through gut dysbiosis induced immunosuppression.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi‑scale immune and spatial profiling of sclerosing adenosis and surrounding breast tissue identifies an immune‑cold field phenotype associated with breast cancer risk.","authors":"Nicole Cruz-Reyes, Hongling Liang, Melody Stallings-Mann, Laura Pacheco-Spann, Bryan M McCauley, Yuanhang Liu, Robert A Vierkant, Jessica L Fischer, Denice L Gehling, Lisa R Seymour, Amy C Degnim, Mark E Sherman, Stacey J Winham, Derek C Radisky","doi":"10.1186/s13058-026-02293-w","DOIUrl":"https://doi.org/10.1186/s13058-026-02293-w","url":null,"abstract":"<p><strong>Background: </strong>Benign breast disease (BBD) is common and confers heterogeneous increases in breast cancer risk; however, risk prediction relies mainly on histopathology and clinical factors. Sclerosing adenosis (SA) is a proliferative BBD lesion associated with an approximately two-fold increase in risk, yet most women with SA never develop breast cancer. We hypothesize that the immune-stromal microenvironment of SA and its surrounding lobular field relates to subsequent invasive breast cancer.</p><p><strong>Methods: </strong>In a nested case-control study within a BBD cohort, we profiled 24 sclerosing adenosis (SA) biopsies (9 developing invasive breast cancer within 15 years, cases; 15 cancer-free at ≥ 15 years, controls). We integrated whole-tissue NanoString gene-expression profiling with multiplex immunofluorescence (MxIF) imaging of SA lesions and surrounding morphologically normal lobules. We measured immune and stromal biomarkers in SA lesions and adjacent lobules, with image analysis masked to case-control status, integrated these data with whole-tissue gene expression, and summarized both microenvironment patterns and the proximity of immune cells to proliferating epithelium.</p><p><strong>Results: </strong>SA biopsies from women who later developed cancer showed a low-immune, high-stromal gene-expression program, whereas controls were enriched for immune signatures. Stromal densities of CD8⁺, CD68⁺ and RUNX3⁺ cells in both lobular stroma and SA lesions mirrored this axis and were markedly lower in cases than controls. Unsupervised clustering identified immune-cold and immune-hot lobule types and four SA lesion field archetypes; immune-hot lobules and immune-hot/epithelium-proliferative lesion fields were enriched in controls. Spatial analyses further showed that immune-hot lobules have stromal immune cells positioned closer to proliferating epithelium and enriched CD27-CD8 microclusters, whereas SA lesions from cases exhibit greater immune-to-Ki67 distances, fewer boundary-proximal CD8⁺ sentinels, and depletion of CD27-RUNX3 and RUNX3-CD8 microclusters.</p><p><strong>Conclusions: </strong>These findings support an association of an immune-cold SA lesion embedded within an immune-cold lobular field phenotype with subsequent invasive breast cancer risk in women with SA, and suggest that spatially organized, RUNX3-rich immune microenvironments may contribute to epithelial surveillance. Validation in larger cohorts will be needed to confirm generalizability and clarify lesion-specific versus field-wide contributions.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic targeting of RAGE/STAT3 signaling abrogates S100A7-driven breast tumorigenicity and immune suppression.","authors":"Pratyusha Ghanta, Ajeet K Verma, Cho-Hao Lin, Manish Charan, Ganesh R Koshre, Shashwat Agarwal, Jonathan Adorno, Ayush Arpit Garg, Tanisha Mukherjee, Wayne O Miles, Jonathan W Song, Sanjay Mishra, Ramesh K Ganju","doi":"10.1186/s13058-026-02281-0","DOIUrl":"10.1186/s13058-026-02281-0","url":null,"abstract":"<p><p>Metastatic breast cancer, particularly triple-negative breast cancer (TNBC), remains a major clinical challenge due to its aggressive behavior and limited therapeutic options. The molecular pathways that drive tumor progression while simultaneously promoting immune evasion are not well defined. Here, we identify S100A7/RAGE signaling as a central oncogenic and immunomodulatory axis that drives TNBC tumorigenicity, metastasis, and immune suppression. In this study, we have shown that S100A7/RAGE signaling plays a vital role in driving invasive TNBC tumorigenicity by activating Stat3 and elevating Serpin-E1 expression. Furthermore, we revealed that combinatorial treatment of Stat3 and RAGE inhibitors synergistically inhibits the tumorigenicity of S100A7-expressing TNBC cells in-vitro by suppressing AKT/MAPK signaling and mitigates the tumor burden, especially distant metastasis in-vivo using TNBC cell lines and a conditional mammary gland-specific S100A7 overexpression bitransgenic mouse model. Moreover, our study also shed light on the dynamic interplay between the S100A7/RAGE/Stat3 signaling pathway and immune cell infiltration within the tumor microenvironment. Remarkably, our findings underscored the potential of combined inhibition to enhance anti-tumor immune responses, fostering the infiltration of anti-tumor MHCII^high and iNOS⁺ macrophages and activated effector CD8⁺ tumor-infiltrating T cells. Moreover, CD8⁺ T cells depletion abrogates the therapeutic benefits of RAGE/Stat3 inhibition by restoring the tumor growth in S100A7 overexpression mice. Importantly, we discovered that S100A7/RAGE signaling modulates anti-tumor macrophage phenotypes by regulating Serpin-E1 expression on TNBC cells. S100A7 regulates Serpin-E1 gene expression by enhancing the direct binding of pStat3 (Ser727) to its promoter. Notably, neutralization of Serpin-E1 in combination with RAGE and Stat3 inhibition increased iNOS expression in macrophages in-vitro and significantly enhanced overall anti-metastatic efficacy in-vivo. Importantly, we found that increased co-expression of S100A7 and Serpin-E1 correlated with worse prognoses in TNBC patients, whereas the presence of iNOS or MHCII genes improved the overall prognosis, especially basal and immunomodulatory subtypes, which also underscores the clinical relevance of targeting these signaling molecules as a promising translational therapeutic strategy for TNBC. Overall, these findings provide new avenues for therapeutic interventions in metastatic TNBC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}