Breast Cancer Risk Biomarkers and Energy Balance

描述（由申请人提供）：肥胖定义为身体质量指数（BMI）>30 kg/m2，目前影响美国31%的成年人，并导致乳腺癌风险增加。解释乳腺癌和绝经后肥胖之间关系的生物学机制包括乳腺组织有丝分裂原水平升高，包括生物可利用的雌激素和雄激素。体重和脂肪过多也与炎性细胞因子的增加有关，炎性细胞因子进一步增加增殖并抑制细胞凋亡。绝经后乳腺癌的可逆性既定风险生物标志物包括增生性乳腺疾病（增生或非典型增生）的组织证据和相关分子标志物（例如，增殖）、血清生物可利用的雌二醇和睾酮、乳房摄影乳腺密度和BMI。干预效应生物标志物基于假定的作用机制提供对干预的生理反应的估计。对于饮食和运动，生物标志物将包括空腹血糖和胰岛素水平，以及炎症标志物，如C反应蛋白，以及体重，体脂百分比和BMI的变化。我们假设，与减肥和运动相关的生物标志物的有利调节将与乳腺癌风险生物标志物的有利调节相关，这最终将与乳腺癌的减少相关。作为解决这一假设的第一步，有必要评估可行性，并以初步的方式确定干预是否对风险生物标志物具有期望的效果。我们的目标是使用由Donnelly及其同事开发和测试的为期六个月的强化饮食/运动/行为改变干预来诱导至少5%的体重减轻，并证明在大多数超重的绝经后妇女中导致高依从性和显著的体重减轻。评估的主要缓解生物标志物将是使用Fabian及其同事开发的用于组织采集和评估的随机乳晕周围细针抽吸（RPFNA）技术调节良性增生上皮的增殖。这两组研究人员的专业知识将结合在这项新的翻译试点研究。具体目标1：确定超重高危绝经后妇女体重减轻5%或以上是否与乳腺癌风险因素（增生灶中Ki-67、细胞形态学、乳腺密度、血清生物可利用雌二醇和睾酮以及SHBG）的有利调节相关。具体目标二：确定干预效应生物标志物（空腹血糖、胰岛素和C反应蛋白）的变化是否与乳腺癌风险生物标志物的变化相关。这项研究的结果可能会导致更大规模的对照试验，以记录运动/饮食/行为改变对乳腺癌发展和全因死亡率风险因素的有益影响。

DESCRIPTION (provided by applicant): Obesity as defined by a body mass index (BMI) >30 kg/m now affects 31% of adults in the United States and results in increased risk for breast cancer. Biologic mechanisms to explain the association between breast cancer and postmenopausal obesity include elevated levels of breast tissue mitogens including bioavailable estrogen and androgens. Excess body weight and fat are also associated with an increase in inflammatory cytokines which further increase proliferation and inhibit apoptosis. Reversible established risk biomarkers for postmenopausal breast cancer include tissue evidence of proliferative breast disease (hyperplasia or atypical hyperplasia) and associated molecular markers (e.g., proliferation), serum bioavailable estradiol and testosterone, mammographic breast density and BMI. Intervention effect biomarkers provide an estimate of the physiologic response to the intervention based on the presumed mechanism of action. For diet and exercise, biomarkers would include fasting glucose and insulin levels, and inflammatory markers such as C reactive protein, in addition to changes in weight, percent body fat, and BMI. We hypothesize that favorable modulation of biomarkers associated with weight loss and exercise will be correlated with favorable modulation in breast cancer risk biomarkers, which will ultimately be associated with a reduction in breast cancer. As a first step in addressing this hypothesis, it is necessary to assess feasibility and to .determine in a preliminary fashion whether the intervention is having the desired effect on risk biomarkers. Our goal is to induce at least a 5% weight loss using a six-month intensive diet/ exercise/behavioral modification intervention developed and tested by Donnelly and colleagues and proven to result in high adherence and significant weight loss in the majority of overweight postmenopausal women. The primary response biomarker assessed will be modulation of proliferation in benign hyperplastic epithelium using the technique of random periareolar fine needle aspirations (RPFNA) for tissue acquisition and assessment developed by Fabian and colleagues. The expertise of these two groups of investigators will be combined in this novel translational pilot study. Specific Aim 1: To determine if a 5% or greater weight loss in overweight high risk postmenopausal women is correlated with favorable modulation of risk factors for breast cancer (Ki-67 in hyperplastic foci, cytomorphology, breast density, serum bioavailable estradiol and testosterone, and SHBG). Specific Aim 2: To determine if change in intervention effect biomarkers (fasting glucose, insulin, and C- reactive protein) correlate with change in breast cancer risk biomarkers. The results of this study will potentially lead to a larger controlled trial to document the beneficial effects of exercise/diet/behavioral modification on risk factors for breast cancer development and all cause mortality.