# Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer

> **NIH NIH P01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $392,373

## Abstract

PROJECT 2: SUMMARY
Breast cancer (BCa) ranks among the leading causes of cancer death in women worldwide. Estrogen Receptor
alpha positive tumors (ER+) are the most common subtype of BCa (~70% of all cases), and are effectively
treated with anti-endocrine therapies that target ER. However, relapse frequently occurs resulting in the
development of endocrine therapy resistance (ETR) and late stage metastatic disease. Substantial evidence
indicates that transcriptional plasticity is a prominent feature of ETR, which provides subpopulations of cancer
cells with the ability to adapt to therapeutic challenges. However, the molecular regulatory networks that govern
anti-estrogen responsiveness in BCa cells remain poorly understood. It is well established that histone lysine
acetylation patterns establish cell type enhancer programs to direct BCa phenotypes. Bromodomain (BRD)
chromatin reader proteins are the primary readers of histone lysine acetylation. Despite being recognized as key
epigenetic mechanisms in cancer and emerging `druggable targets', there are large gaps in our understanding
of the functional relationships that exist between histone acetyllysine and BRDs. In addition, little is known
regarding the role of BRDs in BCa anti-estrogen responses. We have previously characterized the altered
epigenomic profiles in cell models of BCa and ETR. Our published results provide support that epigenome-wide
reprogramming of estrogen-responsive elements is linked to endocrine sensitivity and the acquisition of ETR.
Through an integrated and systematic set of specific aims, we will test the hypothesis that BRDs mediate
endocrine responsiveness in BCa. This project will specifically focus on three main aspects that might have the
potential for improved targeted therapies: The identification of specific bromodomain-containing proteins that can
be targeted to enhance cellular responses to tamoxifen in cancer treatment, determination of the contributions
of BRD-containing proteins to transcriptional plasticity during the early and late phases of ET, and
characterization of the epigenetic landscape of recurrent metastatic ER+ breast cancer to link the global
acetylome with histone binding activity of BRDs. Overall, this work will contribute to our understanding of BCa
epigenetic mechanisms and will facilitate the discovery of new biomarkers for endocrine responsiveness and the
development of new modalities for therapeutic intervention.

## Key facts

- **NIH application ID:** 10107342
- **Project number:** 1P01CA240685-01A1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Seth E Frietze
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,373
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107342

## Citation

> US National Institutes of Health, RePORTER application 10107342, Project 2: Bromodomains as Epigenetic Modulators of Endocrine Responsiveness in ER+ Breast Cancer (1P01CA240685-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107342. Licensed CC0.

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