Talk abstracts

Talk on Friday 02:35-02:50pm submitted by Clarissa Wormsbaecher

In utero estrogenic endocrine disruption alters the stroma to increase collagen deposition, extracellular matrix density, and mammary gland stiffness

Clarissa Wormsbaecher (OSBP, Department of Molecular Genetics, The Ohio State University Comprehensive Cancer Center), Andrea R. Hindman (Department of Molecular Genetics, The Ohio State University Comprehensive Cancer Center), Alex Avendano, Marcos Cortes-Medina, Caitlin E. Jones (Department of Biomedical Engineering, The Ohio State University Comprehensive Cancer Center), Jennifer L. Leight (Department of Biomedical Engineering, The Ohio State University Comprehensive Cancer Center), Jonathan W. Song (Department of Mechanical and Aerospace Engineering, The Ohio State University Comprehensive Cancer Center), Craig J. Burd (Department of Molecular Genetics, The Ohio State University Comprehensive Cancer Center)

Abstract:
In utero exposure to estrogenic endocrine disrupting compounds (EDCs) increases a woman’s lifetime risk of breast cancer. Similarly, mice exposed in utero to the estrogenic EDC bisphenol A (BPA) have increased susceptibility to mammary gland tumors. It is unclear which BPA-induced alterations predispose the mammary gland to cancer transformation. There is a critical need to understand the mechanisms that drive increased cancer risk in order to assess the impact of BPA and BPA alternatives that retain estrogenic activity. We utilize in utero BPA exposure as a model of estrogenic endocrine disruption to study the long-term consequences in the mouse mammary stroma. We performed RNA-seq analysis on fibroblasts isolated from mammary glands of adult female mice that were exposed in utero to BPA or oil control. BPA exposed fibroblasts showed significant transcriptional deregulation, with the extracellular matrix being the most altered cellular component and multiple collagen genes being more highly expressed. This deregulation results in BPA exposed mammary glands displaying an increase in collagen deposition. We found that fibroblasts from BPA exposed mice remodel collagen and decrease fluid permeability of the extracellular matrix, indicative of an increased density in the extracellular matrix. Also, in utero BPA exposure increases mammary gland stiffness. Changes to breast density, stiffness, and collagen deposition are associated with breast cancer risk. Interestingly, the increase in collagen deposition and mammary gland stiffness are only seen in adult mice, and not in prepubescent mice. Additionally, diethylstilbestrol, a strong estrogen known to increase breast cancer risk in humans, increases gland stiffness similar to BPA, while bisphenol S, a weak estrogen and BPA replacement, does not. These data indicate that one target of BPA action is through stromal remodeling that occurs long after the in utero exposure to increase breast cancer susceptibility.

References:
Wormsbaecher et al. Breast Cancer Research (2020)

Keywords: BPA, breast cancer , endocrine disruptors