Bisphenol A (BPA) is a prevalent endocrine-disrupting chemical linked to breast cancer risk, but whether it contributes specifically to the immunosuppressive phenotype of triple-negative breast cancer (TNBC) remains largely unexplored. This hypothesis-generating study aimed to identify candidate molecular targets and pathways that may link BPA exposure to TNBC progression, focusing on the immune microenvironment. We integrated network toxicology, molecular docking, and spatial transcriptomics. Differentially expressed genes (DEGs) from hyperplastic breast tissues (GSE16873) were intersected with high-confidence BPA-associated genes. Core hub genes were identified via protein-protein interaction (PPI) network topology, and their clinical relevance was explored in TNBC cohorts. Molecular docking simulated potential BPA–target interactions. Spatial transcriptomics was used to characterize the spatial distribution of top candidates. Seventeen overlapping genes were identified. SPP1 emerged as a top-ranked hub gene. High SPP1 expression was associated with poorer survival in the basal-like subtype (as a surrogate for TNBC) and correlated with an immunosuppressive microenvironment (macrophage enrichment, lower CD8⁺T-cell abundance). Molecular docking predicted a potential BPA–SPP1 interaction (ΔG = − 6.4 kcal/mol). Spatial transcriptomics revealed pervasive SPP1 enrichment in tumor regions, colocalizing with CD68⁺macrophages and showing limited overlap with CD8A⁺T-cells. In a separate SPP1-low TNBC sample, high-resolution mapping identified ECM-enriched hotspots (e.g., COL3A1, COL1A1) that spatially correlated with macrophage-rich areas. Multivariable Cox regression further demonstrated that SPP1’s prognostic effect was largely mediated by the immune microenvironment. This integrative analysis generates the hypothesis that SPP1 and ECM remodeling may represent candidate features linking BPA exposure to an immunosuppressive microenvironment in TNBC. The proposed BPA–ECM–SPP1 axis warrants future functional validation.
Breast cancer survivors experience health consequences of the disease and its treatment. This study evaluated the incidence of drug use as a proxy for chronic diseases in breast cancer survivors. Data from Cancer Registry of Norway was linked to Norwegian Prescription Database and other national registries for a study population of 1.76 million women born during 1920–90, including 39,039 women diagnosed with breast cancer during 2005–19. Hazard ratios (HRs), with 95
Glutamine metabolism is a vulnerability in triple-negative breast cancer (TNBC), but is buffered by metabolic flexibility. We posited that ionizing radiation (IR) enforces a short-lived glutamine dependency that can be targeted. TNBC cell lines and in vivo models were subjected to IR with or without pharmacological inhibitors of glutamine metabolism. We quantified glutamine flux using stable isotope tracing, DNA repair kinetics, cell cycle progression, apoptosis, tumor growth/metastasis, and changes in the immune microenvironment. IR triggered a radiation-associated anabolic shift (RAAS) characterized by increased ASCT2-mediated glutamine uptake and transient upregulation of glutamine-driven de novo nucleotide synthesis. Isotope tracing revealed that exogenous glutamine supplies nitrogen for the post-IR synthesis of purine precursors, supporting nucleotide biosynthesis following radiation exposure. In vitro, inhibition of ASCT2 with V-9302 abolished RAAS, impaired double-strand break (DSB) DNA repair, caused cell cycle arrest, and increased apoptosis. Compared with other glutamine pathway inhibitors, ASCT2 blockade provided the most consistent radiosensitization across the TNBC lines. In vivo, low-dose V-9302 combined with fractionated radiotherapy slowed primary tumor growth and reduced lung metastasis without causing significant systemic toxicity. Combination therapy increased CD8 + T cell infiltration, pro-inflammatory macrophage polarization, and TNF-α production. IR temporarily induces glutamine dependence in TNBC cells. ASCT2 inhibition (V-9302) exploits this window to block glutamine-driven DNA repair and enhances local anti-tumor immune polarization, leading to radiosensitization and anti-metastatic effects. These results support further studies that combine inhibition of glutamine transport with radiotherapy for breast cancer. Ionizing radiation exposes transient metabolic vulnerability in triple-negative breast cancer by enforcing dependence on glutamine metabolism for stress adaptation and survival. Targeting this induced dependency is a mechanistically grounded therapeutic strategy resolving the existing crisis in glutamine therapy and overcoming the metabolic plasticity in aggressive breast cancer.
To evaluate the antitumor activity and safety of CDK2/4/6 inhibitor culmerciclib plus endocrine therapy as first-line treatment in patients with hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In this single-arm, phase 2 trial, women with HR+/HER- advanced breast cancer with no prior systemic treatments in the metastatic setting received oral culmerciclib 180 mg/day plus an oral aromatase inhibitor (anastrozole 1 mg/day or letrozole 2.5 mg/day) at the investigator’s discretion. The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), clinical benefit rate, disease control rate (DCR), duration of response (DoR), and safety. In total, 39 patients were enrolled and received culmerciclib plus letrozole (n = 21) or anastrozole (n = 18). In the full analysis set (n = 39), the confirmed ORR per RECIST v1.1 was 64.1
Dynamic contrast-enhanced MRI (DCE-MRI) and vascular-related gene expression characterize tumor vasculature the blood vessel network that supports tumor perfusion and drug delivery from macroscopic imaging and microscopic molecular perspectives. We aimed to investigate the complementary vascular heterogeneity captured by these modalities. Paired pre-treatment DCE-MRI and mRNA expression from 932 patients with high-risk stage II/III breast cancer were analyzed. Imaging and gene subgroups were identified separately by k-means clustering of repeatable radiomic features and vascular-related genes. The complementarity of imaging and gene subgroups was assessed by examining their association with each other, comparing their distributions across receptor-defined and PAM50 subtypes, pathway enrichment patterns, associations with pathological complete response (pCR) after adjustment for HR/HER2 status, and distant recurrence-free survival (DRFS) stratification. Three imaging subgroups (image subgroup 1 -subgroup 3: 24.8
