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

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.