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

 描述（由申请人提供）：有大量证据表明，环境干扰化学品（EDCs）启动和促进乳腺癌的发展。在本U 01申请中，我们将研究一个研究不足的暴露敏感性窗口：绝经过渡期。这种转变开始于卵巢功能开始下降，并在绝经期结束，此时卵巢功能停止，导致雌激素水平降低。在这个重要的易感窗口期，妇女健康倡议组织 (WHI)报告说，激素治疗增加了乳腺癌的发病率和死亡率。WHI结果由基于生物学的乳腺肿瘤模型解释;它表明绝经过渡期的激素治疗促进了预先存在的隐匿性病变的生长和最低限度地启动新发肿瘤。我们推测，内分泌干扰物模拟激素治疗，促进绝经过渡期乳腺癌的发展。我们将侧重于多溴联苯醚（PBDEs），因为它们在环境和人体组织中具有持久性，并侧重于双酚A（BPA），因为它广泛用于食品级塑料和热敏纸。这两种内分泌干扰物都被认为是主要的健康问题。我们提出的研究将使我们能够评估这些内分泌干扰物单独和联合对绝经过渡期乳腺癌发展的作用。为了确定机制，我们将应用跨学科的方法，使用细胞培养，从绝经过渡期妇女收集的样本，和小鼠模型。在具体目标1中，我们将使用联合主要研究者Chen博士开发的AroER-Tri筛选细胞培养系统，确定单个和组合的内分泌干扰物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内分泌干扰物对雌激素活性和表观基因组的影响，以及内分泌干扰物与乳腺癌的关联。在具体目标3中，我们将测试这些EDCs对绝经小鼠模型中乳腺病变发展的影响，并与卵巢切除小鼠模型中的影响进行比较。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。这是可能的，因为我们经验丰富，多学科的团队。在具体目标4中，我们将与我们的社区合作伙伴一起，提供一站式基于网络的资源，以获取有关环境暴露和乳腺癌发展的作用的循证材料，特别是在绝经过渡期间。此外，我们将开发，测试和传播教育材料，以多文化多样性的社区。我们将与BCERP的其他多学科团队分享我们的专业知识/工作，以产生有价值的结果，并增加有关EDC暴露机制和影响的相关科学知识。我们希望这项工作能够产生未来的预防战略，以减少或减轻暴露，并促进向公众和决策者有效传播科学合理的调查结果。

 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.