Metformin for Reduction of Obesity Associated Breast Cancer Risk

描述(申请人提供)：高肥胖症是许多疾病的主要危险因素，包括绝经后乳腺癌。有人提出，与目前的体重相比，成年后体重增加与绝经后乳腺癌的相关性更强。前瞻性队列研究表明，大约20%的绝经后乳腺癌病例可归因于成年后体重增加。高肥胖症女性绝经后乳腺癌风险的增加很可能归因于多种代谢紊乱。二甲双胍是一种广泛使用的抗糖尿病药物，它对多种代谢紊乱具有良好的效果，可能会降低高脂肪女性患乳腺癌的风险。此外，二甲双胍可能通过激活AMP激活的蛋白激酶(AMPK)信号通路直接作用于乳腺组织，从而产生抗乳腺增生和诱导细胞凋亡的作用。最近的病例对照和队列研究发现，二甲双胍治疗似乎大大降低了糖尿病患者患癌症的风险，包括乳腺癌。目前正在进行大量二甲双胍用于乳腺癌患者的临床试验。然而，这些研究中的同时或先前的乳腺癌治疗阻碍了对二甲双胍作为单一药物在高危健康妇女中预防乳腺癌的评估。我们建议在超重/肥胖的绝经前女性中进行一项第二阶段的随机、双盲、安慰剂对照试验，这些女性成年后体重有中等到显著的增加，乳房密度高，并且有胰岛素抵抗。这项研究的人群患绝经后乳腺癌的风险增加，并有与乳腺癌风险相关的代谢紊乱的高患病率。总体假设是，二甲双胍干预可以调节高肥胖症女性的乳房风险特征和与乳腺癌风险相关的代谢紊乱。该项目的具体目标是1)确定二甲双胍干预对乳房密度的影响，2)确定二甲双胍干预对代谢紊乱和体重/成分的影响，以及3)探索代谢组学作为系统生物学方法的应用，以评估二甲双胍的化学预防机制。我们建议的研究代表了临床评估二甲双胍在多种疾病风险人群中调节乳腺癌风险的初步步骤。这项研究的结果将对公众健康产生广泛的影响，因为超重和肥胖人口不断增长。由于二甲双胍在降低高危成人糖尿病发病率方面的效果已得到证实，如果它在降低乳腺癌风险方面也被证明发挥了有利的作用，那么它在高肥胖症的高危女性中将有很高的接受度和摄取率。考虑到大多数公众在维持健康生活方式方面面临的挑战，以及二甲双胍对多种代谢紊乱的多效性，二甲双胍可以作为一种综合药理学方法，用于高肥胖高危妇女预防多种疾病。

DESCRIPTION (provided by applicant): High adiposity is a major risk factor for a number of diseases, including postmenopausal breast cancer. It has been suggested that adulthood weight gain is more strongly associated with postmenopausal breast cancer than current weight. Prospective cohort studies suggested that approximately 20% of the postmenopausal breast cancer cases are attributable to adulthood weight gain. The increased postmenopausal breast cancer risk in women with high adiposity is likely to be attributed to multiple metabolic disturbances. Metformin, a widely used antidiabetic drug, exerts favorable effects on multiple metabolic disturbances which may lead to reduction of breast cancer risk in women with high adiposity. In addition, metformin may work directly in mammary tissue through the activation of the AMP- activated protein kinase (AMPK) signaling pathway, leading to an antiprolierative effect and induction of apoptosis. Recent case control and cohort studies found that treatment with metformin appears to substantially reduce the risk for development of cancer in diabetics, including breast cancer. There are a large number of ongoing clinical trials of metformin in breast cancer patients. However, the concurrent or prior breast cancer treatments in these studies hinder the evaluation of metformin as a single agent for breast cancer prevention in at risk healthy women. We propose to conduct a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have experienced moderate to significant adulthood weight gain, have high breast density and are insulin resistant. This study population is at increased risk for postmenopausal breast cancer and has a high prevalence of metabolic disturbances associated with breast cancer risk. The overall hypothesis is that metformin intervention can modulate risk features of the breast and metabolic disturbances associated with breast cancer risk in women with high adiposity. The specific aims for this project are 1) to determine the effect of metformin intervention on breast density, 2) to determine the effect of metformin intervention on metabolic disturbances and body weight/composition, and 3) to explore the application of metabolomics as a systems biology approach to assess the chemopreventive mechanisms of metformin. Our proposed study represents the initial steps in clinical evaluation of metformin for modulation of breast cancer rik in a population at risk for multiple diseases. Findings from this study will have wide public healt impact because of the growing overweight and obese populations. With its demonstrated effect in reducing the incidence of diabetes in high risk adults, metformin would have a high level of acceptance and uptake in at risk women with high adiposity if it has also been shown to exert favorable activities in breast cancer risk reduction. Considering the challenges in maintaining a healthy life style by the majority of general public and the pleiotropic activities of metformin fo multiple metabolic disorders, metformin could be developed as an integrated pharmacological approach for at risk women with high adiposity for prevention of multiple diseases.