Breast Cancer Genomics in Windows of Susceptibility to Endocrine Disruptors

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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.