||5U01ES026137-04 Interpret this number
||Beckman Research Institute/City Of Hope
||Menopausal Transition - a Window of Susceptibility for the Promotion of Breast Cancer By Environmental Exposures
DESCRIPTION (provided by applicant):There is substantial evidence suggesting that environmental disrupting chemicals (EDCs) initiate and promote the development of breast cancer. In this U01 application, we will study an under-investigated window of susceptibility for exposure: the menopausal transition. This transition begins when ovarian function begins to decline and ends at menopause when there is a cessation of ovarian function resulting in low levels of estrogens. During this important window of susceptibility, the Women's' Health Initiative
(WHI) reported that hormone therapy increased both the incidence of and mortality from breast cancer. The WHI results are explained by a biologically-based breast tumor model; it suggests that hormone therapy in the menopausal transition promotes the growth of pre-existing occult lesions and minimally initiated de novo tumors. We hypothesize that EDCs mimic hormone therapy and promote the development of breast cancer during the menopausal transition. We will focus on polybrominated diphenyl ethers (PBDEs) because of their persistence in the environment and human tissue and on bisphenol A (BPA) because of its widespread use in food-grade plastics and thermal paper. Both EDCs are recognized as major health concerns. Our proposed research will allow us to evaluate the role of these EDCs, individually and combined, on the development of breast cancer during the menopausal transition. To determine the mechanisms, we will apply a transdisciplinary approach using cell culture, samples collected from women during the menopausal transition, and mouse models. In Specific Aim 1, we will determine the biologic actions and mechanisms of EDCs, singly and in combination, using the AroER-Tri screen cell culture system developed by the joint-Principal Investigator, Dr. Chen. In Specific Aim 2, we will assess the effects of EDCs in women during the menopausal transition on estrogenic activity and the epigenome, as well as the association of the EDCs and breast cancer. In Specific Aim 3, we will test the effects of these EDCs on the development of mammary lesions in a mouse model of menopause, and compare to the effects in an ovarectomized mouse model. Our transdisciplinary approach will capitalize on the strengths of each study type and allow us to conduct a more comprehensive assessment than any single approach. This is possible because of our experienced, multidisciplinary team. In Specific Aim 4, with our community partners, we will provide a one-stop web-based resource for evidence-based materials on the role of environmental exposures and development of breast cancer, particularly during the menopausal transition. Furthermore, we will develop, test, and disseminate educational materials to multi-culturally diverse communities. We will share our expertise/work with other multi-disciplinary teams in the BCERP to produce valuable results and increase the amount of relevant scientific knowledge on the mechanisms and effects of EDC exposure. We expect this work to result in future prevention strategies to reduce or mitigate exposures and promote effective communication of scientifically sound findings to the general public and policy makers.
Identification of Estrogen-Related Receptor ? Agonists in the Tox21 Compound Library.
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Endocrinology, 2018-02-01 00:00:00.0; 159(2), p. 744-753.