Murguia, S. J. | bioRxiv Science

bioRxiv2026

The Ets transcription factor ETV4 regulates FGF1-dependent proliferation and glycolysis in ER-positive breast cancer

Obesity is a risk factor for estrogen receptor (ER) positive breast cancer. Beyond body mass index, adult weight gain increases breast cancer risk. During weight gain, hypertrophic adipocytes produce fibroblast growth factor 1 (FGF1), which drives estrogen-independent growth of ER-positive tumors. Effects of FGF1 on breast cancer cells include elevated proliferation and enhanced glycolytic activity. We identified the Ets transcription factor ETV4 as a target of FGF1 treatment across multiple breast cancer cell lines. Our objective was to define the role of ETV4 in mediating the tumor-promotional effects of FGF1, to better understand how weight gain and obesity drive breast cancer risk and progression. Here, we determined that ETV4 directly associates with a poor prognosis for patients with ER-positive tumors and positively correlates with FGF1 levels in the context of obesity. We demonstrate that ETV4 is required to mediate the pro-tumorigenic effects of FGF1 on cell proliferation, glycolytic reprogramming, and tamoxifen sensitivity in vitro, and on tumor growth in the presence of estrogen in obese mice. In vitro, ETV4 overexpression enhances proliferation and metabolic activity, mimicking effects of FGF1 on breast cancer cells, but it is not sufficient to promote ER-positive tumor growth before or after estrogen deprivation in vivo in lean females. This study reveals a potentially novel mechanism through which weight gain, characterized by excess FGF1 production, drives the development of aggressive features in the prevalent ER-positive breast cancer subtype.

cancer biology↗

bioRxiv2025

Tamoxifen Targets Wisp2 to Impair Subcutaneous Adipocyte Progenitor Self-Renewal and Adipogenic Differentiation

Breast cancer endocrine therapy, which systemically disrupts estrogen receptor signaling, increases type 2 diabetes (T2D) risk in some women. Sustained treatment with low-dose tamoxifen depletes subcutaneous adipocyte progenitors and promotes glucose intolerance and hepatic lipid deposition in obese female mice. Hyperplastic adipose tissue expansion, especially in subcutaneous depots, preserves metabolic health during a chronic positive energy balance by facilitating nutrient storage and attenuating inflammation. Adipocyte progenitors are renewed in part through Wnt signaling pathway activation, which is altered in women with obesity or T2D. Estrogen receptors are expressed in several adipose cell types, but the distinct actions of tamoxifen in adipocyte progenitors and the mechanisms that explain their depletion during endocrine therapy are not defined. The direct impact of tamoxifen was evaluated in subcutaneous adipose stromal cells from humans and adult mice. Self-renewal, proliferation, and differentiation were measured, and analyses of gene expression and progenitor or preadipocyte populations were performed. Mechanistic insight was gained from primary adipose stromal cells of obese female mice, in which the Wnt1 inducible signaling pathway protein 2 (Wisp2) was lost following endocrine therapy. Wisp2 gain and loss of function studies were carried out in adipose stromal cells to define the link between estrogen signaling and adipocyte progenitor maintenance. We found that tamoxifen treatment disrupts the protection of adipocyte progenitors by estrogen, mediated through suppression of Wisp2. These studies reveal potential metabolic effects of tamoxifen therapy that precede and could drive T2D development in breast cancer survivors.

cell biology↗