Abstract 5377: FGF1 regulates breast cancer growth and metabolic reprogramming through ETV4

Abstract Breast cancer is the most frequently diagnosed cancer in women worldwide. Obesity increases resistance to breast cancer therapies and patient mortality, particularly for estrogen receptor-positive (ER+) tumors that represent 70% of all cases. Adult weight gain in women with obesity, characterized by adipose tissue expansion, is an independent prognostic factor for breast cancer. In a preclinical model, we found that weight gain promoted ER+ tumor growth after endocrine therapy through adipose-derived fibroblast growth factor 1 (FGF1). To determine the underlying mechanisms, we used cultured ER+ breast cancer cells (MCF7, tamoxifen-resistant MCF7 cells, and UCD12 cells) treated with FGF1, combined with gene expression profiling and metabolic analysis. ETS variant 4 (ETV4), which regulates ER activity and cancer cell glycolysis, was the top gene induced by FGF1 in multiple ER+ lines. ETV4 was shown by others to regulate breast cancer metabolism and stemness, contributing to disease progression. We hypothesized that ETV4 mediates the FGF1-dependent effects on breast cancer glycolytic reprogramming in obesity-associated breast tumors. ETV4 was upregulated in human PDX tumors grown in obese versus lean mice. In invasive human breast cancer specimens, high versus low ETV4 expression predicted a shorter recurrence-free survival for patients with ER+ tumors. ETV4 knockdown in cultured endocrine-resistant breast cancer cells prevented the proliferation and induction of glycolytic genes with FGF1 treatment. Conversely, overexpression of ETV4 was sufficient to increase glycolytic gene expression and enzyme activity, as well as cell proliferation. Taken together, our data suggest a mechanism by which FGF1 supports breast cancer endocrine therapy resistance in the context of obesity through ETV4 induction and glycolytic metabolic reprogramming. Understanding this process may aid in designing effective treatments, especially for patients resistant to current ER-targeted therapies. Furthermore, ETV4 may be a biomarker to identify breast tumors with excess FGF signaling and patients at high risk for progression. Citation Format: Barbara Mensah Sankofi, Stevi Johnson Murguia, William L. Berry, Elizabeth A. Wellberg. FGF1 regulates breast cancer growth and metabolic reprogramming through ETV4 [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 5377.