Abstract PS2-11-15: Etv4 mediates fgf1-induced metabolic reprogramming in obesity-driven endocrine-resistant breast cancer

Abstract Breast cancer remains the most commonly diagnosed malignancy among women globally. Obesity significantly worsens patient outcomes and contributes to therapy resistance, particularly in estrogen receptor-positive (ER-positive) subtypes, which account for approximately 70% of all breast cancer cases. In women with obesity, adult weight gain, characterized by adipose tissue expansion, can drive breast cancer risk and progression. In a preclinical model, we previously showed that weight gain promotes ER-positive tumor growth after endocrine therapy through adipose-derived fibroblast growth factor 1 (FGF1). Inhibition of fibroblast growth factor receptor (FGFR) signaling restored sensitivity of tumors to estrogen deprivation in obese mice. To determine how FGFR signaling promoted endocrine resistance, we treated ER-positive breast cancer cells (MCF7, tamoxifen-resistant MCF7, and UCD12) with FGF1 and performed transcriptomic and metabolic profiling. ETS variant 4 (ETV4), a transcription factor known to regulate estrogen signaling and glycolysis, emerged as the most upregulated gene across multiple ER-positive cell lines. Others have shown that ETV4 regulates breast cancer stemness and metabolic reprogramming, implicating it in disease progression. We hypothesized that ETV4 mediates FGF1-induced progression of ER-positive breast tumors in obesity. ETV4 expression was upregulated in human patient-derived xenograft tumors grown in obese versus lean mice. In invasive human breast cancer specimens, high ETV4 expression predicted a shorter recurrence-free survival for patients with ER-positive tumors. Consistent with these findings, analysis of ER-positive breast tumor data revealed a significant positive correlation between FGF1 and ETV4 expression specifically in patients with obesity, and in treatment-resistant tumors at both baseline and in progressive disease, suggesting a clinically relevant FGF1-ETV4 axis in driving obesity-linked disease progression. Mechanistically, ETV4 knockdown suppressed FGF1-induced proliferation and glycolytic gene expression, while ETV4 overexpression increased glycolysis and cell growth. Transcriptomic profiling revealed that ETV4 regulates key tumor-promoting pathways, including glycolysis, epithelial-mesenchymal transition, hypoxia, estrogen signaling, and inflammation. In vivo, ETV4 overexpression enhanced mammary tumor growth in lean mice with low FGF1 levels, indicating it can drive tumor progression independently of FGF1. 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 serve as both a mechanistic driver and a biomarker of poor outcomes, offering a potential therapeutic target for patients with obesity-driven resistance to endocrine therapies Citation Format: B. M. Sankofi, N. S. Thomas, W. L. Berry, E. A. Wellberg. Etv4 mediates fgf1-induced metabolic reprogramming in obesity-driven endocrine-resistant breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-15.