Author ORCID Identifier

https://orcid.org/0000-0001-8008-2525

Date of Award

Spring 5-5-2025

Document Type

Thesis (Ph.D.)

Department or Program

Cancer Biology

First Advisor

Todd W. Miller

Abstract

Breast cancer (BC) is the most common non-keratinocyte cancer diagnosed in women in the United States with approximately 300,000 new cases diagnosed each year. Despite a myriad of treatment options, BC remains the second-most deadly cancer. Estrogen receptor-positive (ER+) BC comprises 60-70% of BC diagnoses and is treated with endocrine therapies that limit ER signaling. Despite endocrine therapy options, ~1/3 of patients experience recurrence within 10-20 years of diagnosis. Novel therapeutic strategies are required to limit BC recurrence-related morbidity and mortality.

Radiotherapy is used as an adjuvant treatment for ER+ BC patients prior to the use of endocrine therapy. Radiation and endocrine therapies individually induce oxidative stress in cancer cells, tumors grown in mice, and human tumors. To investigate the potential to exploit this oxidative stress phenomenon through combination therapy, we tested a panel of ER+ breast cell line models in vitro and in vivo. Endocrine therapy was mimicked using hormone and estrogen deprivation. Radiation therapy was administered with a clinical irradiator. We demonstrated that concurrent treatment with radiation and endocrine therapy induces DNA damage, exacerbates oxidative stress, and significantly slows tumor growth across model systems.

Estrogen therapy was shown to be as effective as anti-estrogen therapy in 1981. It remains under-utilized because of the paradoxical method of promoting ER signaling with therapeutic levels of estrogen and the corresponding lack of mechanistic understanding of its therapeutic action. Estrogen therapy is only effective in ~30% of patients with advanced disease, and lack of a predictive biomarker and rational combination therapies to increase treatment efficacy have limited estrogen use. Our team’s previous work showed that overexpression of ER triggers response to estrogen therapy. When cells overexpressing ER are treated with physiological levels of estrogen, ER drives a hypertranscriptional phenotype that results in increased DNA damage and cell death. I demonstrate how this phenomenon can be exploited by chromatin-modifying agents. Co-treatment with the histone deacetylase inhibitor (HDACi) entinostat and 17beta-estradiol induced DNA damage, acetylation, chromatin accessibility, growth suppression, and synergistically delayed time to tumor recurrence. These collective studies provide pre-clinical evidence for combination therapies that have potential to improve outcomes in patients with ER+ BC.

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