Breast Cancer Genomics in Windows of Susceptibility to Endocrine Disruptors

描述（由申请人提供）：乳腺癌（BC）是一种激素依赖性恶性肿瘤。内分泌干扰物（EDs）是内分泌系统中具有激素活性的外源性物质，可干扰内源性激素的生理功能。动物研究明确表明，ed会破坏乳腺组织的发育，并增加乳腺肿瘤的风险，这取决于暴露的剂量和时间。然而，在人群中直接将EDs和BC联系起来的证据远没有定论。两个主要问题严重限制了将实验室实验转化为人口研究。首先，人类的易感性窗口期还没有被清楚地阐明。其次，大多数动物研究都是一次测试一个ED，其剂量往往比普通人类暴露的剂量高几个数量级。因此，在进行剂量外推时，通常忽略了在人类更可能遇到的复杂ed混合物中可能出现的协同或拮抗剂效应。迫切需要结合现实暴露方案和易感窗口概念的ED-BC关联人群研究。这项拟议的研究采用了一种创新的方法，将动物研究和种群研究结合起来。首先，动物将在6个不同的发育窗口期以生理相关剂量（单独或联合）暴露于三种常用的ed。我们将分析大鼠乳腺组织的全基因组表达和病理特征，以提供EDs的定量和定性生物学效应。研究人员随后将在以人群为基础的长岛乳腺癌研究项目（LIBCSP）中通过使用其广泛的数据库和生物库来验证实验室发现。总体目标是探索环境ed是否在特定的发育窗口中起作用，以及它们是否在导致乳腺癌发展的乳腺组织中独立或协同/拮抗地发挥其生物学效应。本研究结果将为妇女生命过程中环境暴露的影响提供宝贵的信息，可用于指导未来ED暴露和BC的分子流行病学研究。如果这种研究方法提供了预期的信息，它将导致动物模型的发展，该模型可用于研究广泛的EDs和其他外源因素，对未来研究环境暴露于人类疾病的时间具有重要意义。

DESCRIPTION (provided by applicant): Breast cancer (BC) is a hormone-dependent malignancy. Endocrine disrupters (EDs) are exogenous substances with hormonal activity in the endocrine system that disrupts the physiologic function of endogenous hormones. Animal studies unequivocally demonstrated that EDs disrupt development of mammary tissues and increase the risk of mammary tumors depending upon the dose and timing of exposure. However, evidence directly linking EDs and BC in human populations is far from conclusive. Two major issues have seriously limited translation of laboratory experiments into population studies. First, the window of susceptibility has not been clearly elucidated in humans. Second, most animal studies have tested one ED at a time often with doses orders of magnitude higher than common human exposure. Thus dose-extrapolations are usually performed neglecting possible synergistic or antagonist effects in a complex mixture of EDs that humans are more likely to encounter. Population studies of ED-BC associations are urgently needed that incorporate realistic exposure schemes and the concept of susceptibility windows. This proposed study uses an innovative approach of combining both an animal and a population study. First, animals will be exposed to three commonly-used EDs (individually and in combination) in physiological relevant doses at 6 different windows of development. Whole-genome expression and pathological features of rat mammary tissues will be profiled to provide both quantitative and qualitative biological effects of EDs. The investigators will then validate the laboratory findings in the population-based Long Island Breast Cancer Study Project (LIBCSP) through the use of its extensive database and biorepository. The overarching goal is to explore whether environmental EDs are acting in specific developmental windows and whether they exert their biological effects independently or synergistically/antagonistically in breast tissue leading to breast cancer development. Results from this study would provide invaluable information on effects of environmental exposure during women's life course, which may be used to direct future molecular epidemiological studies on ED exposure and BC. Should this study approach provide the information as expected, it will lead to the development of an animal model that can be used to study a wide range of EDs and other exogenous factors with significant implications for future investigations on the timing of environmental exposures to human diseases.