# Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $47,232

## Abstract

PROJECT SUMMARY
Breast cancer (BrCa) is the second leading cause of cancer related deaths in women and the majority of
mortality is due to metastatic BrCa disease. Although our understanding and treatment of advanced breast
cancer has improved, the 5-year survival rate remains at a dismal 22%. Two-thirds of all BrCa is positive for
estrogen receptor (ESR1, ER), which can be exploited by targeted anti-estrogen therapeutics. Unfortunately,
25% of ER-positive primary disease patients and nearly all ER-positive metastatic BrCa patients will go on to
develop treatment refractory disease to these targeted regimens. ER is a prominent component of cancer
progression; thus, it is imperative to understand how advance ER-positive patients confer treatment resistance.
The Lee-Oesterreich lab recently discovered a novel genomic alternation to ESR1, an in-frame translocation
event creating a fusion gene product. A subsequent panel of ESR1 fusions have been discovered and these
ESR1 fusions are estimated to be prevalent in at least 1-5% of advanced ER-positive BrCa disease.
Importantly, these fusions were identified in patients who developed resistance to hormonal therapy.
The functional role of these genomic fusion genes requires further investigation. We will investigate how ESR1
fusions influence cellular proliferation, treatment insensitivity and migration/invasion. Our preliminary data of a
fusion stably expressed in a BrCa cell line exhibited enhanced growth and lack of response to hormonal
treatment. We will also analyze transcriptional and mechanistic changes invoked by ESR1 fusion expression.
Preliminary data of ESR1 fusions transiently transfected into a BrCa cell line exhibited enhanced ER activation
compared to parental and wildtype ER expressing cells. Direct mutagenesis of the fusion partner will better
elucidate the contribution of ESR1 or the fusion partner to global cellular changes. Lastly, we will study the
prevalence of the fusion genes in metastatic refractory disease to determine clinical significance. We will
analyze exosomal RNA isolated from patient blood draws to detect presence of known and novel fusions.
This proposal will ultimately 1) better analyze the metastatic properties of ESR1 fusions both in the presence
and absence of treatment, 2) gain a greater appreciation of ESR1 fusion influence on the transcriptome and
cistrome and lastly 3) define fusion prevalence in advance BrCa and detection of novel fusions over the course
of a controlled clinical trial utilizing anti-estrogen treatment. Successful completion of these Aims will help
inform clinicians and researchers the clinical relevance of ESR1 fusions and if these genomic alternations can
serve as biomarkers for identifying treatment resistant breast cancer and rationale for alternative treatment
strategies.

## Key facts

- **NIH application ID:** 10116161
- **Project number:** 5F30CA250167-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Megan Yates
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,232
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116161

## Citation

> US National Institutes of Health, RePORTER application 10116161, Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer (5F30CA250167-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10116161. Licensed CC0.

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