Date of Award
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
Seth E. Frietze
Abstract
Estrogen receptor-alpha (ERα) is the central driver of estrogen receptor-positive (ER+) breast cancer, where it governs hormone-responsive gene expression programs essential for tumor growth and progression. While endocrine therapies targeting ERα are initially effective, resistance commonly develops through epigenetic reprogramming and altered function of chromatin co-regulators. Chromatin remodeling factors and epigenetic co-regulators have emerged as important modulators of ERα activity, yet their potential as therapeutic targets in ER+ breast cancer and endocrine resistance remains poorly defined.This dissertation investigates the functional and therapeutic relevance of chromatin-associated co-regulators in ER+ breast cancer. Using integrated genomic, proteomic, and pharmacologic approaches, I characterize two classes of epigenetic regulators with emerging roles in endocrine resistance. First, I explore the bromodomain-containing proteins ATAD2 and ATAD2B, which are upregulated in ER+ breast cancers and functionally linked to ERα. CUT&RUN profiling revealed extensive co-localization of ATAD2/ATAD2B at regions enriched with histone H4 lysine acetylation modifications, and proteomic analysis confirmed their association with each other and other complexes. Pharmacologic inhibition with bromodomain inhibitors (BAY-850, GSK8814) selectively impaired proliferation in endocrine-resistant cells, highlighting their potential as therapeutic targets. Second, I characterize BAZ1A, a component of the ISWI chromatin remodeling complex, which has emerged as a clinically relevant factor in hormone-dependent cancers. Multi-cohort analysis associated high BAZ1A expression with poor outcomes in ER+ patients. Using proximity ligation and genomic profiling, I identified a BAZ1A–ERα interaction and demonstrated overlapping chromatin occupancy, suggesting that BAZ1A contributes to ERα-driven transcriptional control and resistance phenotypes. Together, these studies define chromatin remodeling and co-regulatory mechanisms that maintain ER+ breast cancer cell identity in endocrine-dependent breast cancer. By mapping regulatory interactions and pharmacologic vulnerabilities, this work provides a framework for targeting chromatin-based dependencies in ER+ tumors and advancing precision combination therapies to overcome resistance.
Language
en
Number of Pages
196 p.
Recommended Citation
Quinn, Kathleen M., "Functional Analysis Of Chromatin Regulatory Proteins In Estrogen Receptor Positive Breast Cancer" (2025). Graduate College Dissertations and Theses. 2164.
https://scholarworks.uvm.edu/graddis/2164