Timing of Dietary Exposures and Breast Cancer Risk

描述（由申请人提供）： 此应用程序的目标是计划一个项目，与 几个机构，研究饮食暴露的时间是否决定了 对乳腺癌风险的影响。研究的食物成分包括 改变雌激素受体（ER）或其它类固醇活性的那些 受体;即，脂肪酸、植物雌激素、重金属、钙和维生素 D和A。早期的数据表明，发育时期对 雌激素的操纵是胎儿的生命，青春期前和怀孕。我们提出 在子宫内激活ER-cx的饮食成分（脂肪酸，植物雌激素， 重金属）预先启动乳腺癌，使乳腺更敏感 致癌物质。这些相同的暴露也会增加乳腺癌的风险， 母亲，通过增加现有恶性细胞的增殖。在 相反，在怀孕期间暴露于具有抑制ER-α的饮食成分， 表达（钙，维生素D）将降低母亲患乳腺癌的风险 和她的雌性后代儿童时期的雌激素暴露 降低乳腺癌风险。因此，我们建议青春期前接触 一些脂肪酸（鱼油）和植物雌激素可以降低患上 乳腺癌调节饮食时间影响的机制 乳房上的成分可能包括表达的持续变化， ER-cc和肿瘤抑制基因BRCA 1和~53，它们与ER-cc密切相互作用， 雌激素和ER-α。也有可能是这些暴露的时间 饮食成分激活或抑制特定的基因簇， 通过基因芯片技术鉴定。 使用动物模型，我们将测试暴露于某些饮食中的假设， 在怀孕期间的成分增加乳腺癌的风险，通过影响乳房 母亲和雌性后代中的ER-α、BRCA 1和p53水平。我们将进一步 检验青春期前某些饮食暴露会降低乳腺癌发生率的假设。 癌症风险并诱导ER-α、BRCA 1和p53水平的相反变化 比在子宫内暴露后看到的要多。三个不同的人类群体 用于检验饮食可以影响循环雌激素水平的假设 在孕妇和青春期女孩，并影响中间生物标志物， 乳腺癌风险;即月经初潮和乳头生长因子水平 吸出液体这些研究的结果将决定 在怀孕或儿童时期接触与其自身的健康状况 与类固醇受体，可以有长期的保护或有害的影响， 散发性和遗传性乳腺癌风险。最终，我们的结果可能会导致 为某些乳腺癌制定新的预防策略， 例如植物雌激素、脂肪酸、重金属 维生素A和D，以及钙在怀孕期间或儿童。

DESCRIPTION (provided by applicant): 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.