Metformin for Reduction of Obesity Associated Breast Cancer Risk

描述（由申请人提供）：高肥胖是许多疾病的主要危险因素，包括绝经后乳腺癌。有研究表明，成年体重增加与绝经后乳腺癌的相关性比当前体重更强。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体重增加。高肥胖妇女绝经后乳腺癌风险增加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，对多种代谢紊乱具有良好的作用，这可能导致高肥胖女性乳腺癌风险的降低。此外，二甲双胍可能通过激活AMP活化蛋白激酶（AMPK）信号通路直接在乳腺组织中发挥作用，导致抗增殖作用和诱导细胞凋亡。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发生癌症（包括乳腺癌）的风险。有大量二甲双胍在乳腺癌患者中的临床试验正在进行中。然而，这些研究中的同时或既往乳腺癌治疗阻碍了二甲双胍作为单药预防高危健康女性乳腺癌的评价。 我们建议在超重/肥胖的绝经前女性中进行二甲双胍的II期随机、双盲、安慰剂对照试验，这些女性经历了中度至显著的成年体重增加，具有高乳腺密度和胰岛素抵抗。该研究人群绝经后乳腺癌的风险增加，且与乳腺癌风险相关的代谢紊乱患病率较高。总体假设是二甲双胍干预可以调节与高肥胖女性乳腺癌风险相关的乳腺风险特征和代谢紊乱。本项目的具体目的是1）确定二甲双胍干预对乳腺密度的影响，2）确定二甲双胍干预对代谢紊乱和体重/组成的影响，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。 我们提出的研究代表了二甲双胍在多种疾病风险人群中调节乳腺癌风险的临床评价的初步步骤。由于超重和肥胖人口的不断增长，这项研究的结果将对公众健康产生广泛的影响。由于二甲双胍在降低高风险成人糖尿病发病率方面的作用已得到证实，如果二甲双胍也被证明在降低乳腺癌风险方面发挥有利作用，那么二甲双胍在高肥胖风险女性中的接受和摄取水平将很高。考虑到大多数公众维持健康生活方式的挑战以及二甲双胍对多种代谢疾病的多效性，二甲双胍可开发为预防多种疾病的高肥胖风险女性的综合药理学方法。

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.