Breast Cancer : Targets and Therapy最新文献

{"title":"Potential Molecular Links Between Benzophenone-3 and Breast Cancer: Network Toxicology, Machine Learning, Molecular Modeling, and Gene Expression Validation.","authors":"Ziqi Wang, Yingluan Wang, Zhan Cao, Yi Jiang","doi":"10.2147/BCTT.S632531","DOIUrl":"10.2147/BCTT.S632531","url":null,"abstract":"<p><strong>Purpose: </strong>Benzophenone-3 (BP-3) is a widely used ultraviolet filter with potential carcinogenic concern, but its molecular link with breast cancer remains unclear. This study aimed to identify candidate targets and potential molecular links between BP-3 and breast cancer using toxicological prediction, machine learning, molecular modeling, and gene expression analysis.</p><p><strong>Methods: </strong>The ADMET and toxicity profiles of BP-3 were evaluated using PubChem, ADMETlab 3.0, ProTox 3.0, and pkCSM. BP-3-related targets were predicted from ChEMBL, STITCH, and SwissTargetPrediction, while breast cancer-related differentially expressed genes were obtained from GEO datasets. Candidate targets were screened by intersection analysis and examined using GO/KEGG enrichment and PPI networks. Core genes were identified using 127 machine learning model combinations and SHAP interpretation. GSVA, GSEA, TIMER2.0, molecular docking, molecular dynamics simulations, MM-GBSA calculations, and qRT-PCR were used for validation.</p><p><strong>Results: </strong>Seventy BP-3-associated candidate genes related to breast cancer were identified. Among 127 model combinations, Stepglm[both]+SVM showed the best performance, with an average AUC of 0.935, and identified MMP13, ERBB2, and HMGCR as core genes. Functional analyses suggested that these genes were mainly involved in extracellular matrix remodeling, lipid metabolism reprogramming, and energy metabolism regulation. Molecular docking predicted favorable binding poses between BP-3 and the candidate proteins, with docking scores ranging from -5.8 to -8.5 kcal/mol. Molecular dynamics and MM-GBSA analyses indicated stable simulated complexes, with calculated binding free energies below -14.30 kcal/mol. qRT-PCR showed higher expression of MMP13, ERBB2, and HMGCR in the examined breast cancer cell lines than in normal mammary epithelial cells.</p><p><strong>Conclusion: </strong>Integrated computational analyses identified MMP13, ERBB2, and HMGCR as candidate genes potentially linking BP-3 with breast cancer-related molecular features. Molecular docking and molecular dynamics simulations predicted feasible interactions between BP-3 and the corresponding proteins, while qRT-PCR confirmed the differential expression of these genes in breast cancer cell lines. These findings represent computational predictions and correlational evidence rather than proof of direct BP-3 regulation or causation. Direct BP-3 exposure experiments in cellular and animal models are required to establish causal relationships.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"632531"},"PeriodicalIF":3.6,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13674637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149214977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-Dimer Dynamics as a Prognostic and Monitoring Biomarker in Triple-Negative and Metastatic Breast Cancer: A Narrative Review.","authors":"Emmanuel Ifeanyi Obeagu","doi":"10.2147/BCTT.S637558","DOIUrl":"10.2147/BCTT.S637558","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) and metastatic breast cancer (MBC) remain clinically challenging because of aggressive biology, therapeutic resistance, metastatic dissemination, and substantial heterogeneity. D-dimer, a fibrin-degradation product, may capture systemic coagulation and fibrinolytic activation associated with tumour progression and cancer-associated thrombosis.</p><p><strong>Objective: </strong>This narrative review critically examines D-dimer dynamics as a complementary biomarker for prognostic stratification, treatment monitoring, thrombotic risk assessment, and personalized care in TNBC and MBC.</p><p><strong>Results: </strong>Evidence linking D-dimer with tumour burden, metastasis, survival, inflammation, endothelial activation, platelet-tumour interactions, and venous thromboembolism is synthesized. Particular emphasis is placed on longitudinal trajectories, including declining, stable, persistently elevated, and progressively increasing D-dimer patterns, and their potential interpretation alongside imaging, clinical status, inflammatory markers, circulating tumour DNA, and treatment exposure. Major limitations include assay heterogeneity, differences between fibrinogen-equivalent units and D-dimer units, variable reference ranges and cut-offs, and confounding by age, infection, surgery, renal or hepatic dysfunction, immobility, prior thrombosis, and anticancer treatment. Most available evidence remains observational and therefore establishes association rather than causality or proven clinical utility.</p><p><strong>Conclusion: </strong>D-dimer dynamics represent a promising, accessible component of multimodal precision oncology, but should not independently diagnose progression, select anticancer therapy, or determine anticoagulation. Prospective multicentre studies are needed to standardize assays, validate trajectory-based thresholds, integrate D-dimer with multi-omics and artificial intelligence, and determine whether D-dimer-guided monitoring improves outcomes, particularly in resource-constrained settings and diverse African oncology populations globally appropriately.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"637558"},"PeriodicalIF":3.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytoplasmic Basigin Localization is Associated with EMT, Tumor Budding, and Adverse Prognosis in Breast Cancer.","authors":"Xiaoyan Xu, Yaozhong Zhang, Huijuan Fang, Xianwei Xu, Huang Jiang, Shuguang Liu","doi":"10.2147/BCTT.S631016","DOIUrl":"https://doi.org/10.2147/BCTT.S631016","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the clinicopathological significance of Basigin subcellular localization in breast invasive ductal carcinoma, with particular emphasis on its association with epithelial-mesenchymal transition (EMT), tumor budding, and patient prognosis.</p><p><strong>Methods: </strong>A total of 206 cases of primary breast invasive ductal carcinoma were retrospectively collected from Zhengzhou People's Hospital between January 2014 and January 2024. Immunohistochemistry was performed to evaluate the expression and subcellular localization of Basigin, E-cadherin, and Vimentin. Tumor budding was assessed according to the International Tumor Budding Consensus Conference (ITBCC) criteria. Associations between marker expression, clinicopathological parameters, and disease-free survival (DFS) were analyzed. A prognostic nomogram was subsequently constructed based on independent prognostic factors identified by multivariate Cox regression analysis.</p><p><strong>Results: </strong>Predominantly cytoplasmic Basigin localization was significantly associated with larger tumor size, higher Nottingham grade, high-grade tumor budding, advanced TNM stage, and HER2-overexpressing/triple-negative subtypes (all P < 0.05). Tumor budding regions exhibited EMT-associated phenotypes characterized by reduced membranous Basigin staining with relative cytoplasmic redistribution, decreased E-cadherin expression, and increased Vimentin expression. Distinct tumor budding patterns were observed among molecular subtypes, with luminal tumors predominantly showing no budding, HER2-overexpressing tumors showing cluster budding, and triple-negative tumors predominantly showing single-cell budding (all P < 0.05). Kaplan-Meier and multivariate Cox regression analyses demonstrated that Basigin localization (HR = 0.380, 95% CI: 0.171-0.844, P = 0.017), Nottingham grade (HR = 4.839, 95% CI: 2.238-10.466, P < 0.001), tumor budding grade (HR = 37.932, 95% CI: 12.850-111.966, P < 0.001), and molecular subtype (HR = 1.523, 95% CI: 1.164-1.991, P = 0.002) were independent prognostic factors for disease-free survival (DFS). The nomogram demonstrated strong predictive performance, with area under the curve (AUC) values of 0.919, 0.921, and 0.980 for predicting 2-, 3-, and 5-year DFS, respectively.</p><p><strong>Conclusion: </strong>Basigin subcellular redistribution is significantly associated with EMT-associated phenotypes, tumor budding, and adverse prognosis in breast cancer. Assessment of Basigin localization may provide additional prognostic value beyond conventional clinicopathological parameters. A nomogram integrating Basigin localization, tumor budding, histological grade, and molecular subtype may facilitate individualized risk stratification in patients with breast cancer, pending external validation in independent cohorts.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"631016"},"PeriodicalIF":3.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Myristoylation Inhibition by Zelenirstat Disrupts Growth Signalling, Energy Metabolism, and Migration in Triple-Negative Breast Cancer Cells.","authors":"Rony Pain, Erwan Beauchamp, Shawn Duckett, Morris A Kostiuk, Claudia Y Acevedo-Morantes, Heather Mast, Helene Lemieux, Luc G Berthiaume","doi":"10.2147/BCTT.S619042","DOIUrl":"https://doi.org/10.2147/BCTT.S619042","url":null,"abstract":"<p><strong>Background: </strong>Metastatic breast cancer cells rely on oxidative phosphorylation (OXPHOS) for energy production, yet selectively targeting mitochondrial metabolism in cancer cells remains a major therapeutic challenge. Myristoylation, the modification of proteins with the 14-carbon fatty acid myristate by N-myristoyltransferases NMT1 and NMT2, dually impacts cancer cell signalling and metabolism. The pan-NMT inhibitor zelenirstat selectively inhibits these enzymes to prevent the myristoylation of target proteins.</p><p><strong>Methods: </strong>We assessed the effects of zelenirstat on the protein levels and metabolic activity of multiple triple-negative breast cancer (TNBC) cell lines. <i>NDUFAF4</i> knockout (KO) MDA-MB-231 cells were engineered using CRISPR/Cas9. Functional assays included multiple types of respirometry, cell migration measurements, and spheroid formation.</p><p><strong>Results: </strong>Zelenirstat treatment depleted myristoylated complex I assembly factor NDUFAF4 levels in four different TNBC cell lines. This loss effectively abrogated mitochondrial OXPHOS through impairment of complex I, resulting in reduced cellular energy production. Zelenirstat treatment resulted in NADH accumulation, loss of AMPK, and decreased glycolysis. Given that zelenirstat impacted cell signalling and OXPHOS, we further demonstrated that it also significantly impaired migration and invasion. Importantly, both zelenirstat treatment and <i>NDUFAF4</i> KO TNBC MDA-MB-231 cells dramatically reduced mammosphere formation, indicating potent activity against breast cancer stem cells (BCSCs).</p><p><strong>Conclusion: </strong>In addition to the previously shown inhibitory effect of zelenirstat on TNBC cell growth in vitro and in vivo, our new data demonstrate the widespread effects of zelenirstat on both aggressive TNBC cells and BCSCs. These findings highlight the potential of zelenirstat as an anti-metastatic agent, warranting further clinical trial evaluation in patients with TNBC.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"619042"},"PeriodicalIF":3.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the Residual Tumor Burden and Prognosis of Breast Cancer.","authors":"Angela de Salles Rezende, Teresa Cristina Ferreira Gutman, Karin Soares Cunha, Fabiana Resende Rodrigues, Vânia Gloria Silami Lopes","doi":"10.2147/BCTT.S626207","DOIUrl":"10.2147/BCTT.S626207","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer remains a significant global health concern. The residual cancer burden (RCB) system quantifies response to neoadjuvant therapy. This study evaluates pathological response as a prognostic indicator in patients with residual invasive breast carcinoma through a retrospective single-center validation.</p><p><strong>Methods: </strong>In this retrospective cohort study, we analyzed 100 surgical specimens from patients who underwent neoadjuvant therapy and mastectomy at a Brazilian public hospital. The RCB was calculated according to MD Anderson guidelines and classified as RCB-0 (complete response), RCB-I (minimal), RCB-II (moderate), or RCB-III (extensive). Clinicopathological correlations and survival analysis were performed.</p><p><strong>Results: </strong>The cohort was predominantly female (98%) with a mean age of 58.7 years. Invasive carcinoma of no special type was most common (86%). Extensive residual burden (RCB-III) predominated (66%), followed by RCB-II (29%), RCB-0 (3%), and RCB-I (2%). Higher RCB class was significantly associated with higher tumor grade (p< 0.0001), larger tumor size (p< 0.0001), greater lymph node involvement (p< 0.0001), and distant metastasis (p= 0.039). Mortality correlated with increasing RCB (74.6% of deaths were RCB-III). Survival analysis showed a significant difference among RCB classes (p= 0.024), with the most pronounced difference between RCB-II and RCB-III (p= 0.007). The luminal A subtype was more common in RCB-0, while luminal B HER2+ and triple-negative subtypes were more frequent in RCB-III.</p><p><strong>Conclusion: </strong>Within this historical cohort, the RCB index provides valuable prognostic information, effectively stratifying institutional patients based on recurrence and metastasis risk. While its routine adoption in clinical practice is supported to complement risk stratification, conclusions regarding its universal independent value across all classes are bounded by the low number of RCB-0 and RCB-I cases.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"626207"},"PeriodicalIF":3.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological Complete Response and Safety of Neoadjuvant Pembrolizumab-Based Chemoimmunotherapy in Triple-Negative and Hormone Receptor-Low Breast Cancer: A Real-World Cohort Study.","authors":"Baha Sharaf, Tamer Albatsh, Suhaib Khater, Rawaa Alrabie, Abdallah Obidat, Tala Al-Bdour, Mohammad Alzoubi, Mohammad Sami Al-Qannas, Ahmed Alriqib Snr, Bashar Darawsheh, Tala Mzahreh, Ahmad Alazaideh, Huthaifa Albursan, Fahmi A L Nemrawi, Sharif Jehad","doi":"10.2147/BCTT.S636314","DOIUrl":"10.2147/BCTT.S636314","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant pembrolizumab-based chemoimmunotherapy is standard of care for early-stage triple-negative breast cancer (TNBC). Real-world data remain limited outside trial populations, particularly in the Middle East, and hormone receptor (HR)-low tumors (ER/PR 1-10%) are undercharacterised in this setting.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of 149 patients with non-metastatic TNBC or HR-low breast cancer at King Hussein Cancer Center, Jordan (April 2021-September 2024). Primary endpoint was pCR (ypT0/Tis ypN0), analysed across all 149 treatment-initiated patients with the 7 who did not undergo surgery classified as non-pCR; Firth penalised logistic regression identified factors independently associated with pCR. Safety was assessed in all 149.</p><p><strong>Results: </strong>The overall pCR rate was 59.1% (88/149). On Firth penalised multivariable logistic regression, three variables were independently associated with pCR: grade 3 histology (aOR 4.44, 95% CI 1.61-13.66, p = 0.004), pathogenic germline mutation (aOR 3.19, 95% CI 1.26-9.11, p = 0.014), and age younger than 40 years (aOR 2.82, 95% CI 1.20-7.10, p = 0.017). HR-low tumors (n = 15) achieved 66.7% pCR, comparable to HR-negative disease (58.2%). Immune-related adverse events occurred in 44 patients (29.5% of 149); grade ≥3 events in 9 (20.5% of irAE patients; 6.0% of the cohort); permanent immunotherapy discontinuation for treatment-limiting toxicity in 6 (13.6% of irAE patients; 4.0% of the cohort). Hospitalization occurred in 33.6%, predominantly due to febrile neutropenia. At a median follow-up of 27.3 months, 137 of 149 patients (91.9%) were alive and 136 (91.3%) were recurrence-free; all 13 recurrences were distant. Among surgical patients, disease-free survival was 96.6% in the pCR group versus 85.2% with residual disease (log-rank p = 0.011).</p><p><strong>Conclusion: </strong>In this real-world Middle Eastern cohort, pembrolizumab-based chemoimmunotherapy achieved pCR rates consistent with pivotal trial data. Grade 3 histology, pathogenic germline mutation, and age younger than 40 years were independently associated with pCR; the HR-low findings are exploratory. These results support prospective biomarker-driven trials in early TNBC across underrepresented populations.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"636314"},"PeriodicalIF":3.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-Binding Protein CSTF2 Drives Immune Evasion and Malignant Progression in Breast Cancer by Degrading THSD1 mRNA.","authors":"TangXiaoMan Wang, Lei Yan, JiaLi Jiang, Jing He","doi":"10.2147/BCTT.S620942","DOIUrl":"10.2147/BCTT.S620942","url":null,"abstract":"<p><strong>Objective: </strong>Resistance to immunotherapy in breast cancer (BC) is intimately connected to the dynamic tumor immunoediting process. RNA-binding proteins (RBPs) are recognized as pivotal modulators of BC advancement. Cleavage stimulation factor 2 (CSTF2), a core factor involved in mRNA 3'-end maturation, shows significant overexpression in numerous cancers and is correlated with adverse clinical outcomes. However, the precise molecular mechanisms through which it drives malignancy by regulating immunoediting remain incompletely understood.</p><p><strong>Methods: </strong>This study performed a systematic evaluation of CSTF2's expression profile and prognostic significance in BC using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). CSTF2 expression was modulated via knockdown and overexpression approaches to study core malignant traits, such as proliferative capacity and cell migration. The role of CSTF2 in immunoediting was examined through immune landscape analysis and flow cytometry.</p><p><strong>Results: </strong>Integrated bioinformatics identified a regulatory pathway whereby CSTF2 induces transcriptional upregulation of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) by promoting degradation of thrombospondin type-1 domain-containing protein 1 (THSD1) mRNA. The consequent increase in PD-L1 expression potently inhibits CD8⁺ T cell-mediated tumoricidal activity, thereby facilitating immune escape and collectively accelerating malignant progression in BC.</p><p><strong>Conclusion: </strong>This study delineates the detailed molecular mechanisms by which the RBP CSTF2 exacerbates malignant progression, offering fresh theoretical insights and potential targets for targeted immunotherapeutic strategies in BC.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"620942"},"PeriodicalIF":3.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AOH1996, an Inhibitor of PCNA, Sensitises Breast Cancer Cells to Cytotoxic Chemotherapy.","authors":"Radhika Aiyappa-Maudsley, Thomas A Hughes","doi":"10.2147/BCTT.S636967","DOIUrl":"10.2147/BCTT.S636967","url":null,"abstract":"<p><strong>Purpose: </strong>AOH1996 is an inhibitor of proliferating cell nuclear antigen (PCNA). We have assessed efficacies of AOH1996 as a therapeutic, alone and in combination with representative chemotherapies using breast cancer cells of luminal, HER2 positive, and triple negative subtypes.</p><p><strong>Methods: </strong>MCF-7, AU-565, MDA-MB-231, MDA-MB-468, and HCC1143 breast cancer cells were used. Effects of AOH1996, epirubicin, and/or docetaxel on cell proliferation/survival were assessed using MTT and clonogenic assays. DNA damage was evaluated by γ-H2AX immunofluorescence.</p><p><strong>Results: </strong>Single agent AOH1996 treatment reduced proliferation/survival in all cells tested in a dose- and time-dependent manner. Use of AOH1996 in combination with either epirubicin or docetaxel caused significant, consistent and substantial reductions in proliferation/survival that exceeded additive effects for the agents alone. For example, in clonogenic assays using MCF-7 cells, the lowest doses tested of epirubicin and AOH1996 caused inhibition of only 4% and 3% individually, while the combination caused significant inhibition by 34%, representing a 4.8-fold increase on the additive effect. Similarly, using AU-565 cells, docetaxel and AOH1996 caused 6% and 9% inhibition individually, while the combination caused 48%, representing a 3.2-fold increase on the additive effect. Nuclear γ-H2AX foci, indicative of double‑strand DNA damage, were quantified to investigate mechanisms. Combinations of AOH1996 with epirubicin or docetaxel consistently caused significant increases in foci that exceeded additive effects in every cell line, demonstrating that combinations were highly DNA-damaging.</p><p><strong>Conclusion: </strong>Based on our in vitro data, AOH1996 has potential as a breast cancer therapy and causes chemo-sensitisation in combination with chemotherapies standardly used clinically in primary breast cancer. Future in vivo studies are warranted.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"636967"},"PeriodicalIF":3.6,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Consensus-Based Risk Stratification Algorithm for HR+/HER2- Early Breast Cancer to Guide Adjuvant CDK4/6i Therapy: Outcomes from a Multidisciplinary Workshop in India.","authors":"Krishna Mohan Mallavarapu, Rakesh Reddy B, Somashekhar Sp, Pankaj Goyal, Vishwanath Sathyanarayanan, Amit Rauthan, Jyoti Bajpai, Prabhat Ghanshyam Bhargava, Mohit Agarwal, Rakesh Pinninti, Rachana Chennamaneni, Krishna Chaitanya P, Stalin Chowdary Bala, Venkateswar Rao Pydi, Ramavath Dev, P S Dattatreya, Ullas Batra, Govind Babu K, Disha Shetty, Kumardeep Paul, Priya Rathi, Maheboob Basade","doi":"10.2147/BCTT.S620643","DOIUrl":"10.2147/BCTT.S620643","url":null,"abstract":"<p><strong>Purpose: </strong>Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC) is treated with curative intent, but risk of recurrence (RoR) remains a challenge. The identification of high RoR EBC patients is inconsistent, highlighting the need for a simplified approach. This study aimed to develop an evidence-informed, consensus-based tool to support recurrence risk stratification and treatment decision-making in patients with HR+/HER2- EBC, incorporating multidisciplinary perspectives and evolving evidence from guidelines and trials.</p><p><strong>Methods: </strong>Five structured, multidisciplinary workshops were conducted across India, involving 135 experts, to integrate evidence and expert consensus into a practical algorithm for RoR assessment. The workshops included initial polling on clinical practices, followed by case-based discussions and literature review, with post-discussion polling used to capture shifts in expert perspectives.</p><p><strong>Results: </strong>Polling responses demonstrated consensus (defined as ≥70% agreement by experts) that all N1 patients are at a high RoR (94.3%) and that tumors ≥5 cm are associated with high risk (90.0%). Given that low-grade (G1) tumors are associated with a favorable prognosis (low risk) and high-grade (G3) tumors indicate a poorer prognosis (high risk), Ki-67-based treatment decision-making was considered most relevant for the moderate-grade (G2) subgroup. Accordingly, experts agreed that combining tumor grade G2 with Ki-67 assessment improves risk stratification in N0 patients with tumors <5 cm (71.6%). A Ki-67 cut-off of ≥20% was considered critical (96.3%). The experts agreed that adjuvant cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have an invasive disease-free survival (iDFS) advantage in all N1 (93.8%) and high risk N0 (91.1%) patients with HR+/HER2- EBC.</p><p><strong>Conclusion: </strong>The developed algorithm provides a user-friendly framework to facilitate uniform risk stratification and optimize HR+/HER2- EBC treatment in India. Further prospective and real-world validation is required to establish its clinical utility and evaluate its impact on treatment decisions.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"620643"},"PeriodicalIF":3.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BET Protein Degrader ZBC260 Induces Tumor Vascular Reprogramming Through Endothelial Cell Remodeling.","authors":"Deeksha Sharma, Cody G Hager, Max S Wicha, Monika L Burness","doi":"10.2147/BCTT.S626513","DOIUrl":"10.2147/BCTT.S626513","url":null,"abstract":"<p><strong>Purpose: </strong>Endothelial cells regulate angiogenesis, matrix remodeling, and immune responses within the tumor microenvironment, yet endothelial cell heterogeneity across breast cancer subtypes and its regulation by bromodomain and extraterminal domain proteins remain unclear. This study profiled endothelial cells at single-cell resolution in two immunocompetent murine breast cancer models with distinct tumor immune microenvironments: PyMT_FVB/N and D2A1_BALB/c tumors.</p><p><strong>Methods: </strong>Mice were treated intravenously with the bromodomain and extraterminal domain degrader (ZBC260) at 10mg/kg 3 days/week until tumors reached humane endpoints and were harvested. Single-cell RNA sequencing was performed on vehicle and ZBC260 treated tumors (n=3 per condition), and endothelial cell populations were identified and analyzed using Seurat package in R.</p><p><strong>Results: </strong>Six transcriptionally distinct endothelial subpopulations were identified across both breast cancer models, with D2A1 tumors dominated by tip-like and proliferative endothelial cells with strong angiogenic and collagen-producing signatures. ZBC260 reprogrammed endothelial landscape by reducing proliferative, tip-like, and arterial endothelial cells while enriching venous and lymphatic endothelial cells. ZBC260 suppressed hypoxia, glycolysis, and mTORC1 signaling, downregulated angiogenesis and matrix associated pathways and was accompanied by reduced collagen signatures and increased leukocyte adhesion. Cell-cell communication analysis demonstrated that ZBC260 disrupted endothelial cells interactions with tumor and immune cells, by disrupting ligand-receptor communications and attenuating NOTCH, TGF-β, and VEGF signaling networks that sustain angiogenesis and immune suppression.</p><p><strong>Conclusion: </strong>Together, these findings highlight endothelial diversity across breast cancer models and identify ZBC260 as a regulator of tumor endothelial states. ZBC260 reprograms endothelial heterogeneity and remodels the tumor vascular landscape. The transcriptomic and cell-cell communication changes observed are consistent with the establishment of a more immune-permissive tumor microenvironment, supporting the potential of BET degradation as a strategy to complement immunotherapy and improve therapeutic responsiveness in breast cancer.</p>","PeriodicalId":9106,"journal":{"name":"Breast Cancer : Targets and Therapy","volume":"18 ","pages":"626513"},"PeriodicalIF":3.6,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}