Growth Factor Signaling in Obesity Associated Breast Cancer

肥胖相关ER阳性乳腺癌中生长因子信号转导机制的研究 肥胖对于患有乳腺癌的女性来说是一个负面的预后因素。雌激素受体 阳性(ER+)亚型是最常见的诊断亚型，约占病例的70%。流行病学 研究表明，以脂肪组织膨胀为特征的成人体重增加是 肥胖与乳腺癌关系的潜在驱动因素。总体而言，阻碍我们理解 导致肥胖女性乳腺癌进展的原因是缺乏临床前模型 结合肥胖及其合并症、绝经后环境和ER+肿瘤。我有过 创建了饮食诱导肥胖/异种移植(DIOX)模型，以研究乳腺癌的进展和 对治疗的反应。体重增加和脂肪细胞直径与肥胖呈正相关 产生成纤维细胞生长因子(FGF1)，激活肿瘤细胞FGFR1，以及雌激素- ER+乳腺肿瘤的独立生长。我们的首要假设是脂肪膨胀 组织(体重增加)通过脂肪细胞制造成纤维细胞生长因子和 乳腺癌细胞中的FGFR/ER串扰。我们将使用体内和体外模型来研究 脂肪组织对FGF1产生的调节及其在肿瘤FGFR1和FGFR1之间的串扰 1)确定游离脂肪酸(FFA)是否诱导PPARγ- 介导FGF1在肥大脂肪细胞中的表达。2)确定雌激素是否- FGFR1高表达肿瘤的独立生长依赖于ER信号传导。 总体而言，该提案将调查外部因素(宿主脂肪组织FGF1； AIM1)和固有的(肿瘤FGFR1/ER串扰；AIM2)可能导致肥胖相关的肿瘤 使用新的临床前和体外模型系统研究乳腺癌进展。

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.