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的研究 肥胖是女性乳腺癌的一个负面预后因素。雌激素受体 阳性（ER+）亚型是最常见的诊断，占约70%的病例。流行病学 研究表明，以脂肪组织扩张为特征的成人体重增加是一种 肥胖与乳腺癌关系的潜在驱动因素。总的来说，我们理解的障碍是 导致肥胖女性乳腺癌进展的原因是缺乏临床前模型， 结合联合收割机肥胖及其合并症、绝经后环境和ER+肿瘤。我有 创建了饮食诱导的肥胖/异种移植（DIOX）模型来研究乳腺癌进展， 对治疗的反应。体重增加和脂肪细胞直径与脂肪 成纤维细胞生长因子（FGF 1）的产生、FGFR 1的肿瘤细胞活化和雌激素- ER+乳腺肿瘤的独立生长。我们的总体假设是， 组织（体重增加）通过脂肪细胞FGF的产生促进癌症进展， 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FGF 1产生的调节以及由此产生的肿瘤FGFR 1和 ER的具体目的如下：1）确定游离脂肪酸（FFA）是否诱导PPARγ - 介导的FGF 1表达。2)确定雌激素是否- FGFR 1过表达肿瘤的独立生长依赖于通过ER的信号传导。 总体而言，该提案将调查外在因素（宿主脂肪组织FGF 1; Aim 1）和肿瘤内在（肿瘤FGFR 1/ER串扰; Aim 2），可能会驱动肥胖相关性肿瘤。 使用新的临床前和体外模型系统的乳腺癌进展。

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.