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。公共卫生相关性：调查体育活动（PA）对人群中致癌的各个方面的影响，包括努力量化一组非常不同的PA暴露。虽然这种努力是困难的，许多局限性被广泛认识，但有大量证据支持PA与癌症发病率和癌症相关死亡率之间存在负相关关系。在最近发布的2008年美国国立卫生研究院关于体育活动和健康的报告中，该报告回顾了世界上关于体育活动和健康的文献，得出的结论是，有强有力的证据表明，适度到剧烈的体育锻炼与乳腺癌风险的降低有关。大多数报道的队列研究对影响大小的估计为风险降低20% - 80%，一些基于人群的病例对照研究对影响大小的估计为20% - 70%。专家小组得出结论，风险降低可能在20%到40%之间，而且PA对乳腺癌的直接影响与PA与体重控制相关的影响不同。许多专家认为，造成全球超重和肥胖流行的一个主要因素是缺乏体育活动。这导致公共卫生建议个人应该提高他们的PA水平。然而，关注PA来控制体重增加，虽然至关重要，但往往会分散人们对40%的女性体重与身高相适应的事实的关注。重要的是，对于那些将体重保持在可接受范围内以降低癌症风险，但又希望进一步降低风险的人来说，运动强度、持续时间和频率对预防癌症的相对重要性尚不清楚，需要调查。本项目提出的工作专门针对这一妇女群体。正如最近发布的美国国立卫生研究院关于体育活动与健康的报告所指出的那样，关于PA预防和控制癌症的强度和持续时间以及剂量反应的性质的关键转化问题仍未得到解答。鉴于有证据表明，PA似乎也降低了乳腺癌死亡率，并且在癌症治疗期间和之后越来越多地被推荐进行体育锻炼，因此，还建议开展工作，以了解PA如何影响已建立的乳腺肿瘤的生长，并确定PA影响的乳腺癌的分子特征。拟议的临床前实验解决了我们在2008年美国国立卫生研究院体育活动与健康报告中确定的关于PA和癌症的知识差距。获得的数据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公共卫生指南。

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. PUBLIC HEALTH RELEVANCE: Investigations into the effects of physical activity (PA) on various aspects of carcinogenesis in human populations involve an effort to quantify a very heterogeneous set of PA exposures. While such efforts are difficult and many limitations are widely recognized, there is substantial evidence supporting the existence of an inverse relationship between PA and cancer incidence and cancer-related mortality. In a recently released 2008 NIH Report on Physical Activity and Health, which reviewed the world's literature on physical activity and health, it was concluded that the evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous PA. Estimates of the affect size ranged from 20% - 80% reduction in risk from the majority of reported cohort studies and 20% - 70% from a number of population-based case-control studies. The expert panel concluded that the risk reduction is likely to range from 20 to 40%, and that there are direct effects of PA on breast cancer that are distinct from the effects of PA associated with weight control. Many experts contend that a primary factor that accounts for the global epidemic of overweight and obesity is physical inactivity. This leads to the public health recommendation that individuals should increase their level of PA. However, the focus on PA to control weight gain, while critical, tends to distract attention from the fact that 40% of women are an appropriate weight for their height. Importantly, for those individuals who are maintaining body weight in an acceptable range for cancer risk reduction, but who also wish to exercise for further reduction in risk, the relative importance of exercise intensity, duration, and frequency for cancer prevention is unclear and requires investigation. The work proposed in this project specifically addresses this population of women. As noted in the recently released NIH report on Physical Activity and Health, key translational questions remain unanswered about the intensity and duration of PA that prevent and control cancer and the nature of the dose response is unclear. Given evidence that breast cancer mortality also appears to be decreased by PA and that physical activity is increasingly being recommended during and after cancer treatment, work also is proposed to inform understanding of how PA affects the growth of established breast tumors and to identify the molecular characteristics of the breast cancers that PA affects. The proposed pre-clinical experiments address gaps in our knowledge about PA and cancer identified in the 2008 NIH Report on Physical Activity and Health. The data obtained has the potential to facilitate the translation of pre-clinical and clinical research to public health guidelines for PA directed to cancer prevention and control.