The goal of this application is to plan a project, in collaboration with several institutions, to study whether timing of dietary exposures determines their effect on breast cancer risk. Dietary components to be studied include those which alter the activity of the estrogen receptor (ER) or other steroid receptors; i.e., fatty acids, phytoestrogens, heavy metals, calcium, and vitamins D and A. Earlier data have shown that developmental periods most sensitive to estrogenic manipulations are fetal life, prepuberty and pregnancy. We propose that in utero dietary components which activate ER-cx (fatty acids, phytoestrogens, heavy metals) pre-initiate breast cancer, making the mammary gland more sensitive to carcinogens. These same exposures would also increase breast cancer risk in the mother, by increasing the proliferation of existing malignant cells. In contrast, an exposure during pregnancy to dietary components with inhibit ER-a expression (calcium, vitamin D) would reduce breast cancer risk in the mother and her female offspring. Estrogenic exposures during childhood paradoxically reduce breast cancer risk. We therefore propose that prepubertal exposure to some fatty acids (fish oils) and phytoestrogens reduce the risk of developing breast cancer. The mechanisms that mediate the effects of timing of dietary components on the breast perhaps include persistent changes in the expression of ER-cc and tumor suppressor genes BRCAl and ~53, which interact closely with estrogens and ER-a. It is also possible that timing of exposures of these dietary components activate or inactivate specific gene clusters, which can be identified using gene microchip technology. Using animal models, we will test the hypothesis that exposure to some dietary components during pregnancy increases breast cancer risk by affecting mammary ER-a, BRCAl and p53 levels in the mother and female offspring. We will further test the hypothesis that some prepubertal dietary exposures reduce breast cancer risk and induce opposing changes in the ER-a, BRCA 1 and p53 levels than seen after in utero exposures. Three different human populations will be used to test the hypothesis that diet can impact circulating estrogen levels in pregnant women and adolescent girls, and affect intermediate biomarkers of breast cancer risk; i.e. menarche onset and growth factor levels in nipple aspirate fluid. The results obtained in these studies will determine whether exposures during pregnancy or childhood to dietary components that interact with steroid receptors, can have long-lasting protective or harmful effects on sporadic and inherited breast cancer risk. Ultimately, our results may lead to development of novel prevention strategies for some breast cancers, based on dietary intakes of, for example, phytoestrogens, fatty acids, heavy metals, vitamin A and D, and calcium during pregnancy or childhood.
