Timing of dietary exposure and breast cancer risk

描述(由申请人提供)： 流行病学研究并没有一致地将任何特定的饮食成分与乳腺癌风险的增加或降低联系起来。我们认为，这在一定程度上是因为没有完全考虑到饮食暴露的时机在影响风险方面可能比诊断前不久或诊断时的暴露更重要。我们进一步提出，当饮食诱导的生物变化可以改变乳房的发育和功能时，乳房对饮食因素最敏感。这些敏感期包括胎儿生活、青春期和怀孕，在自然暴露于高水平的激素和生长因子后，乳房经历了广泛的增殖。众所周知，类固醇激素及其核受体在乳腺癌中起着核心作用。在这个U54项目中，我们将重点研究与核激素受体相互作用的营养成分的暴露时间。在Hilakivi-Clarke博士(P-I)、Byers博士(P-II)和Makela博士(P-Ill)的三个第一个项目(P-I到P-Ill)中，我们将探索饮食暴露于植物雌激素、n-3多不饱和脂肪酸以及维生素A和维生素D的时机是否会改变乳腺肿瘤的发生，以及调节这些联系的机制。其机制包括雌激素受体(ER)a和ERb、BRCA1、细胞周期蛋白D1和b-连环蛋白的变化。将使用模拟散发性和家族性乳腺癌的动物模型。这些项目将在几个方面相互影响。内万林纳和卢托博士(P-IV)和福格尔霍尔姆博士(试点I)的两个流行病学项目将研究摄入过量能量的时间是否会影响罹患常见乳腺癌的风险，以及防止怀孕期间体重过度增加的饮食干预是否会降低乳腺癌风险。流行病学项目将与P-I和Pilot II互动。Martin博士的Pilot II将研究Era在调节硒对乳房的影响方面的作用。还包括三个核心设施：行政核心、生物统计和微阵列核心和生物资源核心。该计划旨在开发新的方法，通过在怀孕和青春期改变饮食来预防一些乳腺癌。

DESCRIPTION (provided by applicant): Epidemiological studies have not consistently linked any specific dietary component to either an increased or reduced breast cancer risk. We propose that this is partly due to the incomplete consideration that timing of dietary exposures might be more important in affecting the risk than an exposure shortly before or at diagnosis. We further propose that the breast is most sensitive to dietary factors at times when diet-induced biological changes can alter its development and function. These sensitive periods include fetal life, puberty, and pregnancy, when the breast undergoes extensive proliferation following a natural exposure to high levels of hormones and growth factors. Steroid hormones and their nuclear receptors are known to play a central role in breast cancer. In this U54 program, we will focus on studying the timing of exposures to nutritional components that interact with nuclear hormone receptors. In three first Projects (P-I to P-Ill) by Drs. Hilakivi-Clarke (P-I), Byers (P-II) and Makela (P-Ill), we will explore whether timing of dietary exposures to phytoestrogens, n-3 polyunsaturated fatty acids and vitamins A and D alter mammary tumorigenesis and the mechanisms mediating these associations. The mechanisms include changes in estrogen receptor (ER) a and ERb, BRCA1, cyclin D1, and b-catenin. Animal models that mimic both sporadic and familial breast cancers will be used. The projects will interact with each other in several fronts. Two epidemiological projects by Drs. Nevanlinna and Luoto (P-IV) and Dr. Fogelholm (Pilot I) will examine whether timing of excessive energy intake affects the risk of developing familiar breast cancer, and whether dietary intervention to prevent excessive weight gain during pregnancy reduces breast cancer risk. The epidemiological projects will interact with P-I and Pilot II. Pilot II by Dr. Martin will study the role of ERa in mediating the effects of selenium on the breast. Three core facilities are also included: Administrative Core, Biostatistics and Microarray Core, and Bioresources Core. This program aims to develop novel means to prevent some breast cancers by dietary modifications that take place during pregnancy and puberty.