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减少联系起来。我们认为，这部分是由于不完整的考虑，饮食暴露的时间可能是更重要的影响风险比暴露前不久或在诊断。我们进一步提出，当饮食引起的生物学变化可以改变其发育和功能时，乳房对饮食因素最敏感。这些敏感期包括胎儿期、青春期和妊娠期，此时乳房在自然暴露于高水平的激素和生长因子后经历广泛的增殖。已知类固醇激素及其核受体在乳腺癌中起核心作用。在这个U 54计划中，我们将重点研究暴露于与核激素受体相互作用的营养成分的时间。在Hilakivi-Clarke（P-I），Byers（P-II）和Makela（P-III）博士的前三个项目（P-I至P-III）中，我们将探讨饮食暴露于植物雌激素，n-3多不饱和脂肪酸和维生素A和D的时间是否会改变乳腺肿瘤的发生以及介导这些关联的机制。其机制包括雌激素受体（ER）a和ERb、BRCA 1、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作用。Nevanlinna博士和Luoto博士（P-IV）以及Fogelholm博士（Pilot I）的两个流行病学项目将研究过量能量摄入的时间是否会影响发生常见乳腺癌的风险，以及预防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和试点II相互作用。Martin博士的Pilot II将研究ER a在介导硒对乳腺的影响中的作用。还包括三个核心设施：行政核心，生物统计和微阵列核心，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进行饮食调整来预防某些乳腺癌。

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.