Obesity and Endocrine Therapy Resistance in Postmenopausal Mammary Tumorigenesis

描述(申请人提供)：乳腺癌是美国女性中最常见的非皮肤癌类型，由于普遍出现对治疗的抵抗力，乳腺癌仍是治疗方面的一个挑战。在绝经后的女性中，肥胖一直与更高的乳腺癌风险相关，部分原因是血液中雌激素水平的增加。芳香酶抑制剂(Als)是一类有前景的治疗绝经后乳腺癌的药物，它可以减少雌激素的合成。在其他因素中，Akt/mTOR的激活在耐药中起着关键作用。最近的研究表明，内分泌治疗同时使用小分子信号转导抑制剂(STI)抑制mTOR可以恢复内分泌治疗的反应性。建议研究的重点是确定肥胖对阿来曲唑单独或与STI联合应用对乳腺肿瘤反应的影响。这项建议的长期目标包括确定肥胖背景下内分泌治疗抵抗的潜在机制。中心假说是肥胖通过Akt/mTOR依赖的机制导致绝经后乳腺癌的内分泌治疗抵抗。为了实现这些目标，我们将使用MMTV-WNT-1乳腺肿瘤细胞建立绝经后饮食诱导肥胖的小鼠模型。其目的是：(1)表征肥胖对乳腺肿瘤发生和Akt/mTOR信号转导的影响；(2)肥胖对STI的影响；(2)肥胖对乳腺肿瘤发生和Akt/mTOR信号转导的影响；(3)确定肥胖对芳香化酶抑制或与mTOR抑制联合应用对乳腺肿瘤反应的影响。拟议研究的完成将建立绝经后乳腺癌肥胖调节的分子机制，并使人们更好地理解肥胖在内分泌治疗药物中所起的作用。此外，拟议的研究将有助于提高绝经后肥胖乳腺癌患者内分泌治疗的质量和疗效。

DESCRIPTION (provided by applicant): Breast cancer is the most common type of non-cutaneous cancer among women in the United States and continues to provide a challenge regarding treatment due to the common development of resistance to therapy. In postmenopausal women, obesity has consistently been associated with higher breast cancer risk, caused in part by increased circulating estrogen levels. Aromatase inhibitors (Als) are a promising class of drug for postmenopausal breast cancer treatment that decreases estrogen synthesis. Among other factors, the activation of Akt/mTOR plays a critical role in resistance to therapy. Recent studies have demonstrated that endocrine therapy in parallel with mTOR inhibition using small molecule signal transduction inhibitors (STIs) can restore endocrine therapy responsiveness. The focus of the proposed studies is to determine the effect of obesity on mammary tumor responsiveness to the Al letrozole, either alone or in combination with an STI. Long-term goals of this proposal include determining the mechanism underlying endocrine therapy resistance in the context of obesity. The central hypothesis is that obesity contributes to endocrine therapy resistance for postmenopausal breast cancer through an Akt/mTOR- dependent mechanism. To accomplish the aims, we will use a postmenopausal mouse model of diet- induced obesity employing MMTV-Wnt-1 mammary tumor cells. The aims are to: (1) Characterize the impact of obesity on mammary tumor development and Akt/mTOR signaling, (2) Characterize the impact of obesity on STI effects on mammary tumor development and Akt/mTOR signaling, and (3) Determine the impact of obesity on mammary tumor response to aromatase inhibition alone or in combination with mTOR inhibition. Completion of the proposed studies will establish the molecular mechanism underlying the obesity modulation of postmenopausal breast cancer and lead to a greater understanding of the role obesity plays in response to endocrine therapy agents. Furthermore, the proposed studies will contribute to improving the quality and efficacy of endocrine therapy for obese postmenopausal breast cancer cases.