Most prospective epidemiologic studies have shown that a diet that is low in folate and high in alcohol significantly increases the risk of breast cancer (BC), making the methyl (or one-carbon)-deficient diet one of the few modifiable risk factors for BC. Consistently, in the Long Island Breast Cancer Study Project (LIBCSP), a population-based case-control investigation, suboptimal levels of folate, either from low dietary intake or having the variant genotype of the folate-metabolizing gene, MTHFR, confer increased risk of BC. These findings strongly implicate a causal relationship between one-carbon metabolism and BC. However, the mechanism of this association is not well understood. Breast Cancer is a manifestation of abnormal genetic as well as epigenetic changes. One-carbon metabolism facilitates the cross talk between genetic and epigenetic processes by playing critical roles in both DMA methylation and DMA synthesis. The purpose of this proposed study is to investigate whether one-carbon metabolism influences breast carcinogenesis through an epigenetic process. Specifically, we will examine the dietary intake of one-carbon-related micronutrients/compounds (e.g. folate, methionine, choline, vitamins B2, B6, B12, alcohol, etc) in relation to the degree of global hypomethylation and promoter hypermethylation of BC-related genes. We will investigate whether polymorphisms in genes encoding one-carbon-metabolizing enzymes modify the degree/patterns of global and promoter methylation. We propose to utilize the resources of the population- based LIBCSP, making the proposed study highly feasible and cost-effective. A better understanding of the etiological factors contributing to the development of BC could aid in identification of a preventive strategy against the disease. Since epigenetic alterations are reversible and occur early in cancer development, they are promising targets for cancer prevention. To identify the factors that determine the patterns of methylation can provide evidence for the mechanisms of the disease as well as identify at-risk populations in which appropriate diet-based intervention can be provided.