Exercise, Breast Cancer Prevention, and Mechanisms

描述（由申请人提供）：本竞争性更新申请的目标是确定PA对乳腺癌发生作用的机制，这些机制依赖于PA的强度和持续时间，与体重差异无关。提出了三个具体目标：1)PA强度如何抑制致癌过程？将研究一系列PA强度，以测试致癌反应的线性。这将允许评估假设，即PA，按其强度的比例，通过抑制mTOR的激活来抑制乳腺癌的发生。还提出了实验来确定PA是否通过其对胰岛素样生长因子-1 （IGF-1）循环水平的影响来抑制mTOR；2)增加PA持续时间如何降低肿瘤抑制活性？我们的数据清楚地表明，肿瘤抑制活性随着PA持续时间的增加而降低。对PA持续时间的非线性（J型或u型）致癌反应被称为激效，一种生理细胞应激反应。这一目的的目的是确定目标信号通路占激效反应和PA和该途径之间的联系。如果mTOR-IGF-1不能解释，另一种假设集中在sirtuins和叉头转录因子（FOXO）由IL-6；3) PA如何影响乳腺肿瘤肿块的扩张？当乳腺肿瘤达到可测量的大小后，将启动PA，目的是识别因PA而退化的肿瘤亚类（最初根据雌激素和孕激素受体状态和Her-2/Neu表达进行分类）；解释回归的机制将被确定。我们的假设是，PA限制了到达乳腺癌的能量底物的数量，从而通过逆转肿瘤相关的代谢重编程诱导细胞凋亡。拟议的临床前实验有可能促进将临床前和临床研究转化为针对癌症预防和控制的PA公共卫生建议。

DESCRIPTION (provided by applicant): The goal of this competitive renewal application is to define those mechanisms that account for PA's effects on mammary carcinogenesis and that are dependent on PA intensity and duration, and independent of differences in body weight. Three specific aims are proposed:1) How does PA intensity inhibit the carcinogenic process? A range of PA intensities will be investigated to test the linearity of the carcinogenic response. This will permit evaluation of the hypothesis that PA, in proportion to its intensity, inhibits mammary carcinogenesis by suppressing mTOR activation. Experiments are also proposed to determine if PA suppresses mTOR via its effect on circulating levels of insulin-like growth factor-1 (IGF-1); 2) How does increasing PA duration diminish cancer inhibitory activity? Our data clearly indicate that cancer inhibitory activity decreases with increasing PA duration. The non linear (J or U-shaped) carcinogenic response to PA duration is referred to as hormesis, a physiological cellular stress response. The objective of this aim is to identify the target signaling pathway accounting for the hormetic response and the connection between PA and that pathway. If mTOR-IGF-1 is not explanatory, alternative hypothesis centers on sirtuins and forkhead transcription factors (FOXO) by IL-6;and 3) How does PA affect the expansion of tumor mass in mammary carcinomas? After mammary tumors reach a measurable size, PA will be initiated with the objective of identifying subcategories of tumors (initially categorized by estrogen and progesterone receptor status and Her-2/Neu expression) that regress in response to PA; mechanisms that account for regression will be identified. Our hypothesis is that PA limits the amount of energy substrates reaching mammary carcinomas thereby inducing apoptosis by reversing tumor-associated metabolic reprogramming. The proposed pre-clinical experiments have the potential to facilitate the translation of pre-clinical and clinical research to public health recommendations for PA directed to cancer prevention and control.