(PQA-5) DNA methylation and cancer prevention: duration and intensity of exercise

描述(由申请人提供)：据估计，大约八分之一的女性会在一生中的某个时候被诊断出患有乳腺癌。体力活动与降低乳腺癌风险之间存在关联的证据是令人信服的，然而，从强度、持续时间和频率方面来看，降低乳腺癌风险的最佳体力活动数量，以及运动产生这些有益效果的机制仍不清楚。我们的研究小组已经显示了初步的相关数据，在健康的成年人中，体力活动增加与DNA甲基化减少有关--DNA甲基化是癌症风险的一个潜在生物标记物。运动的因果效应--尤其是运动量、强度和持续时间--对甲基化的影响需要在仔细控制的实验设计中进行探索。此外，还没有关于运动引起的甲基化变化持续时间的研究，这是运动建议对公众健康的影响的另一个关键问题。因此，尽管在体力活动和降低患乳腺癌风险之间存在明显的流行病学联系，以及越来越多的证据表明体力活动对DNA甲基化的影响对乳腺癌的发生有影响，但下一步是更好地了解运动对表观遗传修饰的剂量反应关系，这些修饰最终可能会使女性面临乳腺癌的风险。这项拟议研究的目的是探索运动对临床前和容易获得的DNA甲基化生物标志物的影响，这些生物标志物可能与乳腺癌的发展风险有关。我们希望证明运动量在控制运动强度和持续时间方面存在剂量反应关系，这样运动量的增加将与DNA甲基化的更大变化相关，从而提供证据，证明行为(参与有氧运动)和DNA表观遗传变化之间存在机械和因果联系，这可能与乳腺癌风险有关。我们将把这一应用重点放在久坐不动的女性身上，这是一个比经常锻炼的女性患乳腺癌风险更高的群体，并像我们之前的工作一样，研究与乳腺癌相关的基因CpG岛上的DNA甲基化。

DESCRIPTION (provided by applicant): It is estimated that approximately one in eight women will be diagnosed with breast cancer at some point during their lifetimes. The evidence for an association between physical activity and reduced risk of breast cancer is convincing, however, the optimal amount of physical activity for reducing breast cancer risk, in terms of intensity, duration, and frequency, as well as the mechanism by which exercise produces these beneficial effects, remains unclear. Our research group has shown preliminary correlational data linking increased physical activity to decreased DNA methylation-a potential biomarker for cancer risk-among healthy adults. The causal effect of exercise-and in particular exercise volume, intensity, and duration-on methylation needs to be explored in a carefully controlled experimental design. Further, no research has been done on the duration of exercise-induced methylation changes, which is another critical issue with respect to the public health implications of exercise recommendations. Thus while there is a clear epidemiological link between physical activity and reduced risk of developing breast cancer, and increasing evidence for the influence of physical activity on DNA methylation effects on breast cancer development, the next step is to better understand the dose response relationship of exercise on the epigenetic modifications that may ultimately put a woman at risk for breast cancer. The purpose of the proposed study is to explore the influence of exercise on preclinical and easily obtained biomarkers of DNA methylation that are potentially associated with risk for the development of breast cancer. We hope to demonstrate a dose response relationship in exercise volume controlling for both intensity and duration of exercise, such that increases in exercise volume will be associated with greater changes in DNA methylation, providing evidence of a mechanistic and causal link between behavior (participation in aerobic exercise) and epigenetic changes in DNA that are likely to be associated with breast cancer risk. We will focus this application on sedentary women, a group at higher risk for the development of breast cancer than regularly exercising women, and on DNA methylation on the CpG islands of genes associated with breast cancer, as in our previous work.