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Author ORCID Identifier

https://orcid.org/0000-0003-1017-8307

AccessType

Campus-Only Access for One (1) Year

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Animal Biotechnology & Biomedical Sciences

Year Degree Awarded

2021

Month Degree Awarded

September

First Advisor

D. Joseph Jerry

Second Advisor

Karen Dunphy

Abstract

Breast cancer is the second leading cause of cancer mortality among women. Many risk factors for breast cancer are related to estrogen exposure and high serum estrogen levels. Studies have demonstrated the critical role of estrogen in breast carcinogenesis, but less clear how estrogen acts as an initiator of carcinogenesis. Studies have also suggested associations between exposures to endocrine disrupting chemicals may also increase risk of breast cancer. Endocrine disrupting chemicals or xenoestrogens can mimic the effects of estrogen by binding with the receptors and alter the endocrine system. However, there is a lack of detailed mechanistic understanding. The focus of our first study is to investigate the effects of two xenoestrogens – Benophenone-3 (BP-3) and Propyl Paraben (PP) in the breast epithelial cells at concentrations relevant to human exposures and are commonly found in cosmetics, personal care products and sunscreens. While all women are exposed to endogenous and exogenous estrogens, only 1 in 8 women are expected to develop breast cancer suggesting that the cancer-promoting effects of estrogen exposure vary among individuals. Our study demonstrated that E2-induced DNA damage is most pronounced in rodents that are genetically susceptible to mammary tumors and among women who are at high risk of breast cancer. We also found increased E2-induced DNA damage in human breast tissues from women with inherited breast cancer risk alleles affecting DNA double-strand break repair. Our data demonstrate genetic differences in sensitivity to E2-stimulated DNA damage in rodents and that similar variation is observed in normal breast tissues from women.

Lastly, we investigated the mechanism by which E2 and BP-3 induce DNA damage in breast cancer cell lines. We showed that treatment with E2 and BP-3 promotes another non-canonical DNA secondary structure called G quadruplexes (G4s) in ER+ breast cancer cells. The induction of G4 formation and DNA damage with E2 and BP-3 in breast cancer cells is mediated by reactive oxygen species (ROS). Therefore, our data suggest a mechanism in which E2 and BP3 induce R loop stabilization is dependent on ROS which contributes to the formation of DNA G4s and colocalize with sites of DNA damage.

DOI

https://doi.org/10.7275/23975405

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Tuesday, March 01, 2022

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