Growth Factor Signaling in Obesity Associated Breast Cancer

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Growth Factor Signaling in Obesity-Associated ER-positive Breast Cancer Obesity is a negative prognostic factor for women with breast cancer. The estrogen receptor positive (ER+) subtype is the most commonly diagnosed, representing ~70% of cases. Epidemiological studies have implicated adult weight gain, characterized by adipose tissue expansion, as one underlying driver of the obesity-breast cancer relationship. Overall, a barrier to our understanding about what drives breast cancer progression in women with obesity is the lack of preclinical models that combine obesity and its comorbidities, the postmenopausal environment, and ER+ tumors. I have created a diet-induced obesity/xenograft (DIOX) model to study breast cancer progression and response to therapy. Weight gain and adipocyte diameter were positively associated with adipose production of fibroblast growth factor (FGF1), tumor cell activation of FGFR1, and estrogen- independent growth of ER+ breast tumors. Our overarching hypothesis that expanding adipose tissue (weight gain) promotes cancer progression through adipocyte FGF production and FGFR/ER crosstalk in breast cancer cells. We will use in vivo and in vitro models to investigate the regulation of FGF1 production by adipose tissue and the resulting crosstalk between tumor FGFR1 and ER in the following specific aims: 1) Determine whether free fatty acids (FFAs) induce PPARγ - mediated FGF1 expression in hypertrophic adipocytes. 2) Determine whether estrogen- independent growth of FGFR1 overexpressing tumors depends on signaling through ER. Overall, the proposal will investigate the contribution of factors extrinsic (host adipose tissue FGF1; Aim1) and intrinsic (tumor FGFR1/ER crosstalk; Aim2) to the tumor that may drive obesity-associated breast cancer progression using novel preclinical and in vitro model systems.