Loading...
Functional Analysis Of Chromatin Regulatory Proteins In Estrogen Receptor Positive Breast Cancer
Quinn, Kathleen M
Quinn, Kathleen M
Citations
Altmetric:
License
License
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.
Description
Date
2025-01-01
Student Status
Journal Title
Journal ISSN
Volume Title
Type of presentation
Collections
Files
Research Projects
Organizational Units
Journal Issue
Citation
DOI
Advisor(s)
Department
Cellular, Molecular and Biomedical Sciences