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

确定子宫内雌激素内分泌干扰对乳腺僵硬和乳腺癌风险的作用

• 批准号: 10457430
• 负责人: Craig J Burd
• 金额: $ 34.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457430
• 关键词: Acute; Adult; Age; Animal Model; Architecture; Automobile Driving; Biochemical; Biochemistry; Biological; Biological Markers; Biological Models; Biology; Biophysics; Breast; Breast Cancer Risk Factor; Chemical Exposure; Chemicals; Clinical; Clinical Research; Collagen; Consensus; Data; Daughter; Deposition; Development; Diethylstilbestrol; Disease susceptibility; Elasticity; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Exposure; Epigenetic Process; Epithelial; Estrogen Receptor alpha; Estrogens; Event; Exhibits; Exposure to; Extracellular Matrix; Fibroblasts; Foundations; Genetic; Goals; Hormones; Incidence; Individual; Industrial Product; Life; Link; Maintenance; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measures; Mediating; Molecular; Molecular Biology; Molecular Target; Mothers; Outcome; Pathogenicity; Permeability; Pesticides; Phenotype; Play; Population; Predisposition; Pregnant Women; Risk; Role; Screening procedure; Signal Transduction; Stromal Change; Structure; Study models; Testing; Therapeutic Uses; Tissue Recombination; Tissues; Uterus; Woman; biomarker identification; bisphenol A; breast density; breast tumorigenesis; cancer initiation; cancer risk; dichlorodiphenyltrichloroethane; estrogenic; estrogenic activity; in utero; mRNA Expression; malignant breast neoplasm; mammary epithelium; mammary gland development; mouse model; potential biomarker; prenatal exposure; therapeutic target; tumorigenesis

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.

项目概要/摘要 雌激素内分泌干扰化合物 (EDC) 在农药和其他工业中普遍存在 产品在环境中长时间保持活性。那些妇女的女儿 产前接触雌激素 EDC 二乙雌酚 (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 最终驱动肿瘤发生的详细机制仍然很大程度上未知。这种缺乏 理解限制了准确确定个体和群体雌激素 EDC 风险的能力 曝光。该提案的目标是确定 EDC 暴露与癌症之间的联系机制 并提供能够评估 EDC 暴露风险的生物标志物。 我们已经在乳腺基质内发现了许多由 EDC 驱动的重编程事件。 这些事件包括胶原蛋白沉积增加，导致乳腺硬度增加和 细胞外基质（ECM）的通透性降低。已显示出类似的基质组织变化 增加动物模型中的癌症易感性，并且似乎与 EDC- 驱动肿瘤发生。我们的首要假设是雌激素 EDC 会改变体内平衡 乳腺内的信号传导导致 ECM 变化，最终导致乳腺癌。我们 建议使用明确的小鼠模型系统来测试这一假设，其具体目标如下：1) 描述雌激素 EDC 诱导的机制，有助于乳腺基质分子和 组织改变。 2) 评估雌激素 EDC 诱导的基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 EDC 影响基质改变，基质改变如何改变组织稳态信号传导 乳腺发育并确定基质成纤维细胞内的表观遗传重编程事件 使 EDC 暴露从子宫传播到成年。我们期望此分析将提供 为理解环境 EDC 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。