Defining the role of in utero estrogenic endocrine disruption on mammary gland stiffness and breast cancer risk

项目摘要/摘要 雌激素内分泌干扰物(EDCs)广泛存在于农药和其他工业中。 它们在环境中长时间保持活跃的产品。她们的女儿是 产前暴露于雌激素EDC己烯雌酚(DES)和二氯二苯基三氯乙烷(DDT) 表现出患乳腺癌的风险增加。尽管EDC暴露与癌症风险之间存在联系 最终推动肿瘤发生的详细机制(S)在很大程度上仍不清楚。这种缺乏 了解限制了准确确定雌激素类EDC的个体和人群风险的能力 曝光。这项提议的目标是确定EDC暴露与癌症之间的联系机制(S 并提供能够评估EDC暴露风险的生物标志物。 我们已经在乳腺间质中发现了一些由EDC驱动的重编程事件。 这些事件包括胶原沉积增加，导致乳腺僵硬和 降低细胞外基质(ECM)的通透性。类似的间质组织改变也被显示出来 在动物模型中增加癌症易感性，并似乎提供了与EDC的生物学联系- 推动了肿瘤的发生。我们的主要假设是雌激素样的内分泌细胞改变体内平衡。 乳腺内的信号导致细胞外基质的变化，最终导致乳腺癌。我们 建议使用定义良好的小鼠模型系统来验证这一假设，具体目标如下：1) 表征雌激素样内皮细胞诱导的机制(S)，有助于乳腺间质分子和 组织改变。2)评估雌激素EDC诱导的间质改变对乳房的贡献 癌症风险。这些研究将回答该领域的几个关键问题，包括雌激素活性如何 影响间质改变，间质改变如何改变组织内稳态信号 乳腺发育和确定间质成纤维细胞中的表观遗传学重编程事件 从子宫到成年传播EDC的接触。我们预计这一分析将提供 为理解环境内皮细胞如何驱动肿瘤发生以及提供 EDC暴露的潜在生物标志物和治疗靶点。

PROJECT SUMMARY / ABSTRACT Estrogenic endocrine disrupting compounds (EDCs) are ubiquitous in pesticides and other industrial products where they remain active in the environment for extended periods. Daughters of women who were exposed prenatally to the estrogenic EDC diethystilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) exhibit an increased risk of breast cancers. Despite a link between EDC exposure and cancer risk the detailed mechanism(s) that ultimately drive tumorigenesis remains largely unknown. This lack of understanding limits the ability to accurately determine the individual and population risk of estrogenic EDC exposures. The goal of this proposal is to determine the mechanism(s) that links EDC exposure to cancer and to provide biological markers capable of evaluating EDC exposure risk. We have identified a number of EDC-driven reprogramming events within the mammary gland stroma. These events include increased collagen deposition that results in increased mammary gland stiffness and decreased permeability of the extracellular matrix (ECM). Similar stromal tissue changes have been shown to increase cancer susceptibility in animal models and appear to provide a biological connection to EDC- driven tumorigenesis. It is our overarching hypothesis that estrogenic EDCs alter the homeostatic signaling within the mammary gland leading to ECM changes that ultimately drive breast cancer. We propose to test this hypothesis using a well-defined mouse model system with the following Specific Aims: 1) Characterize the estrogenic EDC-induced mechanism(s) that contribute to breast stromal molecular and tissue alterations. 2) Evaluate the contribution of estrogenic EDC-induced stromal alterations to breast cancer risk. These studies will answer several key questions in the field including how the estrogenic activity of EDCs impact stromal alterations, how stromal alterations alter tissue homeostatic signaling during mammary gland development and determine the epigenetic reprogramming events within stromal fibroblasts that propagate an EDC exposure from the womb through adulthood. We expect that this analysis will provide a strong foundation for understanding how environmental EDCs drive tumorigenesis as well as provide potential biomarkers and therapeutic targets for EDC exposure.