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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109753-05
Application #
7800444
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Ross, Sharon A
Project Start
2006-06-26
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$464,927
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
White, Alexandra J; Chen, Jia; Teitelbaum, Susan L et al. (2016) Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer. Environ Res 145:93-100
McCullough, Lauren E; Chen, Jia; Cho, Yoon Hee et al. (2016) DNA methylation modifies the association between obesity and survival after breast cancer diagnosis. Breast Cancer Res Treat 156:183-94
McCullough, Lauren E; Chen, Jia; White, Alexandra J et al. (2015) Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity. Int J Cancer Clin Res 2:
McCullough, Lauren E; Chen, Jia; White, Alexandra J et al. (2015) Global DNA Methylation, Measured by the Luminometric Methylation Assay (LUMA), Associates with Postmenopausal Breast Cancer in Non-Obese and Physically Active Women. J Cancer 6:548-54
White, Alexandra J; Chen, Jia; McCullough, Lauren E et al. (2015) Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study. Cancer Causes Control 26:1791-802
Khankari, Nikhil K; Bradshaw, Patrick T; McCullough, Lauren E et al. (2014) Genetic variation in multiple biologic pathways, flavonoid intake, and breast cancer. Cancer Causes Control 25:215-26
Bradshaw, Patrick T; Khankari, Nikhil K; Teitelbaum, Susan L et al. (2013) Nutrient pathways and breast cancer risk: the Long Island Breast Cancer Study Project. Nutr Cancer 65:345-54
Xu, Xinran; Gammon, Marilie D; Hernandez-Vargas, Hector et al. (2012) DNA methylation in peripheral blood measured by LUMA is associated with breast cancer in a population-based study. FASEB J 26:2657-66
Cho, Yoon Hee; Shen, Jing; Gammon, Marilie D et al. (2012) Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients. Breast Cancer Res Treat 131:197-205
Xu, Xinran; Gammon, Marilie D; Jefferson, Elizabeth et al. (2011) The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study. Epigenetics 6:1276-83

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