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Investigating the Effect of Endocrine Disruptors on Breast Cancer Risk

Wormsbaecher, Clarissa
http://rave.ohiolink.edu/etdc/view?acc_num=osu1650550408367306

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Breast cancer is the number one diagnosed cancer in females. It is estimated that over 287,000 women will be diagnosed with breast cancer and that over 43,000 women will succumb to breast cancer in the U.S. alone in 2022. Environmental exposures are strongly linked to development of breast cancer, but the relationship between the environment and breast cancer initiation is complex. Endocrine disrupting compounds (EDCs) are compounds found in the environment which alter normal hormone signaling. Many of these compounds are estrogenic and alter normal estrogen signaling. One such compound is Bisphenol A (BPA). BPA is found in water bottles, epoxy resin used as food can linings, dental composites and sealants, and thermal receipt papers. In utero exposure to estrogenic EDCs increases a woman’s lifetime risk of breast cancer. Specifically, in utero exposure to BPA alters mammary gland morphology and increases susceptibility to mammary gland tumors, but it has been unclear which BPA-induced alterations predispose the mammary gland to cancer transformation. With the increased usage of BPA and BPA alternatives, and due to the delayed impact of in utero exposures to synthetic estrogens on breast cancer susceptibility (>40 years), it is unclear how the increased exposures to EDCs will impact the human population. 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. Studies have suggested that BPA acts through the mammary stroma. 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 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. The fibroblasts isolated from BPA exposed mammary glands remodel collagen differently compared to control, which decreased fluid permeability of the extracellular matrix and was indicative of an increased density in the extracellular matrix. Also, in utero BPA exposure induces a more stiff mammary gland. Changes to breast density, stiffness, and collagen deposition are all associated with breast cancer risk, therefore this data reveals a mechanism by which in utero BPA exposure increases breast cancer risk in adulthood. 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. Correlative evidence in the field suggests that in utero BPA action occurs through ERα in the developing stroma (in the mammary mesenchyme). Herein, we generated a mesenchymal ERα knockout mouse to test the requirement of mesenchymal ERα for BPA-induced increase in mammary tumorigenesis. We found that knocking out mesenchymal ERα delays epithelial elongation in prepubescent mice, but that knockout of mesenchymal ERα has no effect on epithelial elongation and mammary gland development in adulthood. Additionally, mesenchymal ERα is required for proper reproductive tract development, and without it, these mice have altered estrus cycling. When determining the requirement of mesenchymal ERα for BPA-induced increase in mammary tumorigenesis, we found that mice with mesenchymal ERα had worse outcomes for tumor free survival and overall survival compared to those without mesenchymal ERα. Our data provide experimental evidence that BPA does signal through mesenchymal ERα to worsen outcomes in tumor studies.
Craig Burd (Advisor)
Mark Parthun (Committee Member)
Takeshi Kurita (Committee Member)
Matthew Ringel (Committee Member)
120 p.
Biology; Biomedical Research; Developmental Biology; Endocrinology; Environmental Health; Genetics; Molecular Biology; Oncology
endocrine disrupting compounds; EDCs; bisphenol A; BPA; estrogen receptor alpha; ERα; breast cancer

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Citations

  • Wormsbaecher, C. (2022). Investigating the Effect of Endocrine Disruptors on Breast Cancer Risk [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650550408367306

    APA Style (7th edition)

  • Wormsbaecher, Clarissa. Investigating the Effect of Endocrine Disruptors on Breast Cancer Risk. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1650550408367306.

    MLA Style (8th edition)

  • Wormsbaecher, Clarissa. "Investigating the Effect of Endocrine Disruptors on Breast Cancer Risk." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650550408367306

    Chicago Manual of Style (17th edition)

osu1650550408367306
© 2022, some rights reserved.Creative Commons License Investigating the Effect of Endocrine Disruptors on Breast Cancer Risk by Clarissa Wormsbaecher is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.