Using repeated measures of exposure and the long follow-up in the Nurses' Health Study (1976 to 2004), we propose a series of analyses relating specific aspects of diet, nutritional status, and postmenopausal use to breast cancer incidence and survival among women with breast cancer. DNA samples from cohort numbers will be used to evaluate associations between functional important polymorphisms and risk of breast cancer and potential gene-diet interactions. Specific exposures will also be related to tumor characteristics using pathology blocks that have been collected from incident breast cancer cases. Dietary hypotheses include that low folate intake and blood levels increase breast cancer risk, in particular tumors characterized by negative estrogen receptor status and aberrant methylation of the genes for this receptor and p16; that dietary fiber and specific types and sources of fiber, flavonoids, overall antioxidant intake, conjugated linoleic acid (CLA), and decreases in adiposity each reduce risk. We further hypothesize that high dietary glycemic load and intakes of heterocyclic amines from cooked meat, N-3 fatty acids from fish, and (after a long latent period) total fat each in increase risk. Polymorphisms in genes related to specificity dietary exposures (MTHFR, manganese SOD, and NAT1/2) will be examined in relation to breast cancer directly and as interactions with the corresponding dietary factors. We also propose to evaluate the type and dose of post-menopausal hormone preparations in relation to overall risk of breast cancer and estrogen receptor status of tumors. Finally, we hypothesize that high intake of dietary fat reduces survival among women with breast cancer, but that high intake of protein, regular physical activity, and avoidance of weight gain each increase survival. Because of the prospective design with repeated measures of exposure, long follow-up, and large numbers of breast cancer cases (over 5,000 cases for most dietary analyses), these analyses will provide important data for women and their health providers attempting to reduce risk of breast cancer.
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