Abstract 6333: Interactions between endocrine-targeting therapies and short-chain fatty acids in reducing ER+ breast cancer

Abstract Emerging evidence highlights the gut microbiome as a key player in estrogen receptor-positive (ER+) breast cancer development and recurrence, with breast cancer patients often exhibiting altered gut microbial profiles. Although oral endocrine-targeting therapies have proven effective in treating and preventing ER+ breast cancer recurrence, the risk of therapeutic resistance and tumor recurrence remains decades post-diagnosis. Whether these endocrine targeting therapies interact to shift the gut microbiome and whether modifying diet-microbe-metabolite interactions could enhance the efficacy of these therapies remains largely unexplored. Preliminary data indicate that supplementing with bacterial-derived metabolites, particularly short-chain fatty acids (SCFAs), may impact ER+ breast cancer by influencing tumor initiation, progression, and response to treatment. In both chemical-carcinogen-induced and spontaneous genetic MMTV-PyMT murine models of mammary tumorigenesis, exogenous SCFA supplementation increased tumor-free survival and reduced tumor multiplicity in the context of a high-fat diet. Additionally, in a 4T1.2ER+ syngeneic murine breast cancer model, exogenous administration of SCFA butyrate alone reduced tumorigenesis by modulating apoptosis (cleaved caspase 3) and immune infiltrate (F4/80 macrophages and infiltrating CD8+ T-cells). Further, exogenous administration of all three SCFA (butyrate, acetate, propionate) in mice on high-fat, low-fiber diet significantly reduced tumor growth and enhanced tamoxifen anti-tumor efficacy. SCFA interventions modulated tumor proliferation (Ki67), tumor apoptosis, and enhanced anti-tumor immunity (infiltrating CD8+ T-cells). Plasma butyrate levels were negatively correlated with breast cancer patient BMI, suggesting obesity interactions regulate gut microbial metabolite generation. To explore direct drug-microbe interactions we used an ex vivo colonic bioreactor and human donor fecal samples, we show that the aromatase inhibitor (AI) letrozole increased the proportional abundance of several SCFA-producing microbes. Moreover, metagenomic sequencing of DNA isolated from fecal samples obtained from postmenopausal breast cancer patients before and 3 months after AI treatment (NCT05030038) further revealed shifts in gut microbial populations, including increases in the proportional abundance of SCFA-producing species. These changes were associated with decreased circulating inflammatory cytokines. These findings suggest that SCFAs may suppress breast carcinogenesis, promote endocrine-targeting therapy responsiveness, and AI may directly modify SCFA-producing microbiota in breast cancer patients. SCFA may represent a promising adjunctive strategy to improve the outcomes of endocrine-targeting therapies for ER+ breast cancer patients. Citation Format: Alana Arnone, Adam S. Wilson, Valerie S. Payne, Katherine Ansley. Interactions between endocrine-targeting therapies and short-chain fatty acids in reducing ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6333.