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Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Molecular and Cellular Biology
Year Degree Awarded
Month Degree Awarded
D. Joseph Jerry
Sallie S. Schneider
Cancer Biology | Developmental Biology
Breast cancer is the second leading cause of cancer related death among women and the most prevalent cancer type in women worldwide. Many risk factors for breast cancer are related to estrogen exposure and all involve prolonged or high levels of estrogen exposure. However, estrogen exposure during early pregnancy reduces breast cancer risk by up to 50%. Estrogen’s paradoxical role in both contributing to and reducing breast cancer risk is still not understood. We hypothesized that a subset of women may be more sensitive to estrogen exposure, and the following experiments were designed to test this hypothesis and determine if sensitivity to estrogen is due to estrogen receptor levels or downstream regulation of estrogen signaling.
Using a human breast ex-vivo model, donor human breast explants were treated with control or estrogen for 4 days and then transcriptional and functional responses were compared between individuals. Responses to estrogen varied among individuals, although estrogen receptor target gene expression, progesterone receptor protein expression, proliferation, and irradiation induced apoptotic responses were not significantly correlated with varied estrogen receptor levels. These results indicated that there are variable responses to estrogen exposure among individuals but that these responses do not appear connected to estrogen receptor expression levels. Our second model, conditionally immortalized primary human mammary epithelial cells, also demonstrated variable responses in luciferase reporter assays with estrogen and xenoestrogen treatment.
Lastly, we examined estrogen-induced responses in 4 inducible ERα HMEC cell lines. While all were able to activate luciferase reporter assays and expressed ERα protein, only 3 out of 4 demonstrated a proliferation response to estrogen. Expression of estrogen receptor target genes, however, was not regulated by estrogen treatment. Conditioned media assays demonstrated that this proliferation was driven by intracellular factors. As others have implicated the pioneer factors FOXA1 and GATA3 in generating estrogen-induced responses, we examined mRNA expression of these coregulators in our cells and found no correlation with estrogen-induced proliferation. Collectively, our work demonstrated individual variation in estrogen receptor expression and estrogen and xenoestrogen-induced responses. Further, our results suggest intracellular factors, such as estrogen receptor coregulators, are important for modulation of estrogen-induced biological responses.
Black, Amye L., "INTER-INDIVIDUAL VARIATION IN RESPONSE TO ESTROGEN AND IMPLICATIONS FOR BREAST CANCER RISK" (2020). Doctoral Dissertations. 1976.