In utero availability of the essential nutrient, choline, and mammary cancer risk

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DESCRIPTION (provided by applicant): The goal of the proposed studies is to test the hypothesis that prenatal availability of choline modulates the risk of development of mammary carcinoma. This notion is based on evidence that prenatal availability of choline has long-lasting biological effects persisting into adulthood and old age. Choline is an essential nutrient for humans. Because fetal development constitutes a period of increased demand for choline, US dietary guidelines call for increased choline intake by women during pregnancy. In our previous studies, that focused on the effects of prenatal availability of choline on brain development and cognitive functions, we found that rats supplemented with choline during the second half of gestation exhibited improvements in memory which lasted throughout their entire lifespan. These effects correlated with molecular, biochemical, and structural changes in brain. In adult rats, lack of dietary choline causes hepatocarcinoma and is the only nutritional deficiency that leads to cancer in the absence of any known carcinogens. We found that choline deficiency in adulthood increased mammary cancer risk while choline supplementation reduced it in rats treated with procarbazine as a carcinogen. Aim 1 is designed to test the hypothesis that prenatal choline availability (deficiency, sufficiency, and supplementation) modulates the development of the mammary gland in female rats as monitored by histological techniques and patterns of gene expression determined by microarrays. To assess the mechanisms of the latter changes we will test the hypothesis that prenatal availability of choline alters DNA methylation of the regulatory elements of genes, based on the evidence that choline, via its action as a donor of methyl groups, can alter DNA methylation and gene expression in vivo. We will study DNA methylation of selected genes that are regulated by this process and whose expression we found to be modulated by prenatal availability of choline (e.g. insulin-like growth factor II, Igf2). Aim 2 is designed to test the hypothesis that prenatal availability of choline modulates mammary carcinogenesis using as a model Sprague Dawley rats treated with 7, 12-dimethylbenz[a]anthracene (DMBA), a carcinogen that causes tumors similar to human breast cancers. Tumor incidence and tumor development will be determined. Premalignant as well as malignant changes in mammary tissues from these animals will be evaluated using histological and microarray techniques. In a pilot study of this kind we observed trends for a slowed disease progression in prenatally choline-supplemented rats and an acceleration of tumor growth by prenatal choline deficiency. The mammary tumors from prenatally choline-supplemented rats had higher expression of cyclin D1, STATS, and prolactin receptor and lower expression of STATS mRNA as compared to the tumors from the control- and prenatally choline-deficient subjects. This proposal, prepared in response to an NIH Program Announcement, uses the R21 Exploratory Developmental grant mechanism designed to provide support for the early stages of research development such as projects to assess the feasibility of a novel area of investigation. The ultimate goal of our studies is to relate our results to humans and to develop perinatal nutritional strategies which could benefit people.