Exercise, Breast Cancer Prevention, and Mechanisms

描述(申请人提供)：体力活动与乳腺癌风险之间存在负相关关系，现有证据表明，预防癌症是由于体力活动对成年人体重增加的影响，与之不同，也与之相关。关于体育活动本身是如何影响癌症风险的，人们知之甚少。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。体力活动的这一子集通常被称为锻炼。在这一应用中，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，其强度、持续时间和频率对乳腺癌发生的影响。我们的目标描述在以下目标中：1)确定抑制乳腺癌发生的启动后阶段的运动强度、持续时间和频率。对于那些将体重保持在可接受的范围内以降低癌症风险，但也希望锻炼以进一步降低风险的人来说，运动强度、持续时间和频率对癌症预防的相对重要性尚不清楚，需要进行调查。这项工作将使用一种新开发的运动模型，其中通过食物强化来维持跑步行为。这种方法不仅避免了使用不利的刺激来保持对锻炼方案的遵守，而且还允许操纵摄入的饮食能量与锻炼期间消耗的能量的比率。2)研究运动对胰岛素样生长因子(IGF)和皮质酮的影响，以及它们在乳腺组织和乳腺癌前病变和恶性病变中可能影响的信号通路。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至少在一定程度上是抑制活性的原因。因此，拟议的实验将集中在对这些分子的研究上。3)评估与运动相关的细胞增殖、凋亡和/或血管生成的改变是否可能是癌症抑制活性的原因。基于这些结果和目标2的发现，研究最有可能解释运动抑癌活性的分子途径(S)。关于运动对参与致癌的细胞过程的错误调节的影响，目前还没有什么信息。对于已确定的细胞过程(增殖、凋亡或血管生成)，将进行分子研究。建议的临床前实验应该提供关于运动对生物标记物的影响以及与癌症终点相关的机制的关键信息。这些数据应该有助于将临床前和临床研究转化为降低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.