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.