Menopausal transition - a window of susceptibility for the promotion of breast cancer by environmental exposures

 描述(申请人提供)：有大量证据表明，环境干扰性化学物质(EDCs)会引发和促进乳腺癌的发展。在U01的应用中，我们将研究一个未被充分研究的暴露易感性窗口：绝经过渡。这种转变从卵巢功能开始下降开始，到绝经期卵巢功能停止，导致雌激素水平降低时结束。在这一易受影响的重要时期，妇女健康倡议 世界卫生组织(WHI)报告称，激素治疗增加了乳腺癌的发病率和死亡率。WHI结果是由一个基于生物学的乳腺肿瘤模型解释的；它表明，绝经过渡期间的激素治疗促进了先前存在的隐匿性病变的生长，并最大限度地减少了新生肿瘤的发生。我们假设内分泌细胞类似激素治疗，并在绝经过渡期间促进乳腺癌的发展。我们将重点介绍多溴二苯醚(PBDEs)，因为它们在环境和人体组织中的持久性，以及双酚A(BPA)，因为它在食品级塑料和热敏纸中广泛使用。这两个EDC都被认为是主要的健康问题。我们建议的研究将使我们能够评估这些内分泌细胞单独和联合在绝经过渡期间乳腺癌发展中的作用。为了确定这种机制，我们将采用跨学科的方法，使用细胞培养、从更年期妇女身上收集的样本和小鼠模型。在具体目标1中，我们将利用联合首席研究员陈博士开发的AroER-Tri Screen细胞培养系统，确定单个和联合使用的EDCs的生物学作用和机制。在具体目标2中，我们将评估绝经过渡期女性的内分泌细胞对雌激素活性和表观基因组的影响，以及内分泌细胞与乳腺癌的关系。在具体目标3中，我们将在绝经小鼠模型中测试这些EDCs对乳腺病变发展的影响，并与去卵巢小鼠模型中的效果进行比较。我们的跨学科方法将利用每种研究类型的优势，使我们能够进行比任何单一方法更全面的评估。由于我们经验丰富的多学科团队，这是可能的。在具体目标4中，我们将与我们的社区合作伙伴一起，提供一站式网络资源，以获取关于环境暴露和乳腺癌发展的作用的循证材料，特别是在更年期过渡期间。此外，我们将向多元文化社区开发、测试和传播教育材料。我们将与BCERP中的其他多学科小组分享我们的专业知识/工作，以产生宝贵的成果，并增加有关EDC暴露的机制和影响的相关科学知识。我们期待这项工作将产生未来的预防战略，以减少或减轻暴露，并促进向公众和政策制定者有效传播具有科学依据的研究结果。

 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.