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

更年期过渡——环境暴露促进乳腺癌易感性的窗口期

基本信息

批准号：
9307836
负责人：
Shiuan Chen
金额：
$ 97.79万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307836
关键词：
Advocacy Age Aromatase Autopsy Biological Biological Assay Breast Breast Cancer Model Breast Cancer survivor California Case-Control Studies Cell Culture System Cell Culture Techniques Cell Line Cell Proliferation Cells Chemical Exposure Chemicals Chemoprevention Clinical Communication Communities DNA Methylation Data Development Dose Educational Materials Educational workshop Endocrine Disruptors Environment Environmental Exposure Environmental Impact Environmental Risk Factor Estradiol Estrogen Receptors Estrogens Estrone Food Future General Population Genes Genetic Transcription Goals Growth Health Hormone Responsive Hormones Human In Situ In Vitro Incidence Individual Injection of therapeutic agent Intervention Joints Knowledge Lesion MCF10A cells Mammary Neoplasms Mammary gland Measures Menopause Menstruation Methylation MicroRNAs Modeling Mus Ovarian Paper Plasticizers Plastics Policy Maker Population Study Postmenopause Predisposition Prevention strategy Principal Investigator Process Progesterone Receptors Reporting Research Research Design Resources Risk Role Sampling Serum Testing Time Woman Women&apos s Health Work base bisphenol A breast cancer diagnosis carcinogenicity environmental chemical epigenome estrogenic activity evidence base experience experimental study hormone therapy human tissue in vivo malignant breast neoplasm mortality mouse model multidisciplinary online resource ovarian failure persistent organic pollutants polybrominated diphenyl ether public health relevance receptor expression sound teacher tumor tumor growth web site

项目摘要

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.

描述（由应用提供）：有大量证据表明，环境破坏化学物质（EDC）启动并促进乳腺癌的发展。在此U01应用程序中，我们将研究一个易感性不足的暴露窗口：更年期过渡。当卵巢功能开始下降并在更年期结束时，卵巢功能停止导致雌激素的水平较低时，这种过渡就开始了。在这个重要的易感性窗口中，妇女的健康计划（whi）报道了马酮治疗增加了乳腺癌的发病率和死亡率。 WH结果由基于生物学的乳腺肿瘤模型来解释。这表明在更年期过渡中的雌激素治疗促进了先前存在的神秘病变的生长和最小的从头肿瘤。我们假设EDC模拟了雌激素治疗，并促进了更年期过渡期间乳腺癌的发展。由于它们在环境和人体组织以及双苯酚A（BPA）中，我们将重点关注多溴的二苯基醚（PBDES），因为它在食品级塑料和热纸中的宽度用于宽度。两种EDC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EDC在更年期过渡期间乳腺癌发展的单独和合并的作用。为了确定机制，我们将使用细胞培养的跨学科方法，在绝经期间从女性那里收集的样本和小鼠模型。在特定的目标1中，我们将使用由联合主要研究员Chen博士开发的AROER-TRI筛选细胞培养系统来确定EDC，单独和结合的EDC的生物学作用和机制。在特定的目标2中，我们将评估EDC在更年期过渡期间女性对雌激素活性和表观基因组的影响，以及EDCS和乳腺癌的关联。在特定的目标3中，我们将测试这些EDC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，并使我们能够比任何一种方法进行更全面的评估。这是可能的，因为我们的经验，多学科团队。在特定目标4中，与我们的社区合作伙伴一起，我们将提供基于网络的一站式资源，用于基于循证的材料，涉及环境暴露和乳腺癌发展的作用，尤其是在绝经期间。此外，我们将开发，测试和传播教育材料，向多元文化的多样化社区。我们将与BCERP中的其他多学科团队分享我们的专业/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的数量。我们预计这项工作将导致未来的预防策略减少或减轻暴露，并促进向公众和政策制定者进行科学合理发现的有效沟通。