Exercise, Breast Cancer Prevention, and Mechanisms

描述（由申请人提供）：已经提出了身体活动与乳腺癌风险之间的负相关关系，现有证据表明，身体活动对癌症的保护是由于其对成人体重增加的影响不同且相关的影响。人们对体育活动本身如何影响患癌症的风险知之甚少。鉴于目前职业活动减少的趋势，大多数妇女将需要利用娱乐活动来体验健康益处。身体活动的这一部分通常被称为锻炼。在这个应用中，我们建议在一个广泛使用的实验模型系统中研究运动的三个主要组成部分，它的强度，持续时间和频率对乳腺癌发展的影响。我们的目标如下：1)确定运动强度、持续时间和频率对乳腺癌起始后阶段的抑制作用。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。一种新开发的运动模型将用于这项工作，其中跑步行为是通过食物强化来维持的。这种方法不仅避免了使用不利刺激来维持对运动方案的依从性，而且还允许操纵饮食能量摄入相对于运动期间消耗的能量的比例。2)研究在Aim 1中描述的条件下运动对胰岛素样生长因子（IGF）和皮质酮的影响，以及它们可能影响乳腺组织和恶性前期和恶性乳腺病变的信号通路。我们假设运动对胰岛素样生长因子（IGF）和皮质酮的影响可能是抑制活性的原因，至少是部分原因。因此，拟进行的实验将集中在这些分子的研究上。3)评估运动相关的细胞增殖、凋亡和/或血管生成的改变是否可能解释癌症抑制活性。基于这些结果和Aim 2的发现，研究最有可能解释运动抑癌活性的分子途径。关于运动对参与癌变的细胞过程的错误调节的影响的信息很少。对于确定的细胞过程（增殖、凋亡或血管生成），将进行分子研究。提出的临床前实验应提供有关运动对生物标志物和与癌症终点相关的机制的影响的关键信息。这些数据应有助于将临床前和临床研究转化为减少癌症风险的公共卫生建议。

DESCRIPTION (provided by applicant): An inverse association between physical activity and risk for breast cancer has been proposed and available evidence indicates that protection against cancer is due to effects of physical activity that are distinct from as well as related to its effects on adult weight gain. Little is know about how physical activity per se affects the risk for cancer. Given current trends towards reduced occupational activity, most women will need to use recreational activity to experience health benefits. This subset of physical activity is generally referred to as exercise. In this application we propose to study the influence of three principal components of exercise, its intensity, duration, and frequency, on the development of breast cancer in a widely used experimental model system. Our objectives are described in the following aims: 1) Determine the exercise intensity, duration, and frequency that inhibits the post initiation stage of mammary carcinogenesis. 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. A newly developed model for exercise in which running behavior is maintained by food reinforcement will be used for this work. This approach not only circumvents the use of adverse stimuli to maintain compliance to an exercise protocol, but also permits manipulation of the ratio of dietary energy ingested relative to the amount of energy expended during exercise. 2) Investigate the effects of exercise per the conditions described in Aim 1 on insulin-like growth factor (IGF) and corticosterone and a signaling pathway they may affect in mammary tissue and in pre-malignant and malignant mammary pathologies. We hypothesize that the effects of exercise on insulin-like growth factor (IGF) and corticosterone are likely to account, at least in part, for inhibitory activity. Therefore, the proposed experiments will focus on the investigation of these molecules. 3) Evaluate whether exercise-related alterations in cell proliferation, apoptosis and/or angiogenesis are likely to account for cancer inhibitory activity. Based on those results and findings from Aim 2, investigate the molecular pathway(s) most likely to account for the cancer inhibitory activity of exercise. Little information exists concerning the effects of exercise on the misregulation of cellular processes involved in carcinogenesis. For the cellular process (proliferation, apoptosis or angiogenesis) identified, molecular studies will be conducted. The preclinical experiments proposed should provide critical information concerning the effects of exercise on biomarkers and mechanisms in relation to cancer endpoints. These data should facilitate the translation of pre-clinical and clinical research to public health recommendations for cancer risk reduction.