Breast Cancer Genomics in Windows of Susceptibility to Endocrine Disruptors

乳腺癌基因组学对内分泌干扰物的易感性窗口

基本信息

批准号：
8665931
负责人：
Jia Chen
金额：
$ 47.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665931
关键词：
Address Animals Biological Carbon Communication Communities Complex Mixtures Databases Development Dietary intake Dose Endocrine Disruptors Endocrine system Environmental Exposure Epidemiologic Studies Exogenous Factors Exposure to Future Gene Expression Genes Genetic Polymorphism Genome Goals Hormonal Hormones Human Individual Investigation Laboratories Laboratory Finding Lead Life Cycle Stages Link Long Island Breast Cancer Study Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Metabolism Methylation Modeling Molecular Molecular Profiling Neonatal Phenols Physiological Policy Maker Population Population Study Predisposition Principal Investigator Rattus Research Design Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Risk Scheme Testing Time Tissues Translations Woman animal model development biobank cancer genomics endocrine disruptor exposure exposed human population human disease innovation malignant breast neoplasm member neglect outreach phthalates population based prenatal exposure programs promoter research study urinary

项目摘要

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.

描述（由申请人提供）：乳腺癌（BC）是一种依赖激素的恶性肿瘤。内分泌不顾问（EDS）是内分泌系统中具有激素活性的外源物质，破坏了内源激素的生理功能。动物研究明确地表明，EDS会破坏乳腺组织的发展，并根据暴露的剂量和时间增加乳腺肿瘤的风险。但是，直接联系人口中的ED和BC的证据远非结论性。两个主要问题严重限制了将实验室实验转化为人群研究。首先，在人类中尚未清楚地阐明易感性的窗口。其次，大多数动物研究经常一次测试一次，其剂量比普通人暴露高。因此，通常进行剂量 - 二十一个，以忽略人类更有可能遇到的复杂的EDS混合物中可能的协同或拮抗作用。迫切需要进行ED-BC关联的人群研究，以结合现实的暴露计划和易感性窗口的概念。这项拟议的研究采用了一种创新的方法来结合动物和人群研究。首先，在6种不同发育窗口处的生理相关剂量中，动物将暴露于三种常用的ED（单独和组合）。大鼠乳腺组织的全基因组表达和病理特征将被分类，以提供ED的定量和定性生物学作用。然后，研究人员将通过使用其广泛的数据库和生物验证方式来验证基于人群的长岛乳腺癌研究项目（LIBCSP）中的实验室发现。总体目标是探索环境ED在特定的发育窗口中的作用，以及它们是否在乳腺组织中独立或协同/拮抗作用，导致乳腺癌发育。这项研究的结果将提供有关妇女生命过程中环境暴露影响的宝贵信息，这些信息可用于指导未来关于ED暴露和BC的分子流行病学研究。如果该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ED和其他外源性因素，对未来对环境暴露于人类疾病的时机的研究产生了重大影响。