Biology subjects

Wellberg, E. A.

Publications and source records attributed to Wellberg, E. A..

5 recordsLinked to original sources

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↗

bioRxiv2025

Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts

Estrogen receptor positive (ER+) breast cancer represents a significant proportion of breast cancer brain metastasis but remains understudied. Here, we report that FGFR1-amplification, a well-established driver of ER+ breast cancer endocrine resistance, promotes ER+ breast cancer brain metastatic colonization in young and aged female mice, through both canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promoted breast cancer brain metastasis in estrogen-treated young mice, but FGF2 levels and signaling decreased in the brain with aging and estrogen-depletion. Neuronal and astrocytic NCAM1, which remain unchanged in young and aged brains, promoted adhesion to neurons, migration, and growth of ER+ cells, suggesting that interactions with astrocytes and neurons facilitate early ER+ breast cancer brain metastasis colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively blocked early colonization but not late-stage brain metastases, suggesting prevention of FGFR1+ brain metastases as a window of opportunity for FGFR1 inhibitors.

cancer biology↗

bioRxiv2021

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNF, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multifactorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

cancer biology↗

bioRxiv2020

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use associated with larger breast adipocyte diameter only in women with a BMI >30 kg/m2. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from adipose tissue, endocrine therapies induced adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. Metformin or pioglitazone, glucose lowering drugs used to treat diabetes, prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies act via ER to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

physiology↗