# Estrogen receptor fusions genes as drivers of endocrine resistance in breast cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $550,223

## Abstract

Anti-estrogen therapy is key to the prevention and treatment of estrogen receptor (ER, ESR1) positive breast
cancer, but therapy resistance occurs in up to a half of cases resulting in incurable advanced disease. We
recently reported recurrent ESR1 fusions in advanced endocrine-resistant breast cancers, with loss of ligand
binding representing a canonical model of drug resistance. Intriguingly, cases with ESR1 fusions co-occurred
with ESR1 base-pair mutations, likely pointing towards convergent evolution under prolonged anti-estrogen
therapy. Evidence from our group and others suggest that ESR1 fusions are found in ~10-20% of advanced
breast cancers, however, many ESR1 fusions harbor different 3’ partner genes, making detection challenging.
To determine prevalence, we will comprehensively re-analyze the ESR1 genomic locus in data from metastatic
breast cancers. Further, we have developed and optimized a target capture sequencing assay capable of
comprehensively detecting ESR1 fusions in both tumor biopsies and ctDNA. We have identified endogenous
ESR1 fusions that are expressed in two patient derived xenografts (PDX) (ESR1-LPP and ESR1-NFkB) and in
an ER-positive breast cancer cell line MDA-MB-435 (ESR1-SYNE1). We will express ESR1 fusions in recently
generated patient-derived organoids (PDO) which show ER expression and response to estrogen that is equal
or greater than traditional cell lines. Intriguingly, different ESR1 fusions show stark differences in activity,
implicating a role for the 3’ gene partner in modulating activity of the ESR1 N terminal domain (NTD). The NTD
is an intrinsically disordered protein within the transactivation domain, and using a novel integrative-biophysics
approach, we recently reported that while it is mostly disordered, it can adopt an unexpectedly compact
conformation which in turn directs interaction with coregulators. In this proposal we seek to test the hypothesis
that ESR1 fusions are key mediators of endocrine-resistance and breast cancer mortality. We will employ
EnRich to determine the prevalence of ESR1 fusions (and point mutations) in national and international clinical
cohorts of advanced endocrine resistant breast cancer and monitor when they arise during therapy using
longitudinal collection of plasma and ctDNA analyses. We will use patient-derived organoid models of breast
cancer to compare and contrast the activity and function of ESR1 fusions and point mutations relative to wild-
type ER and translate this into in vivo patient derived organoid xenograft (PDOX) and (PDX) models to assess
endocrine resistance. We will study mechanism of action, including the effects on DNA binding and
transcriptional activity, and the role of the 3’ partner gene in any gain of function activities. Finally, we will
examine the structure-function of ESR1 fusions focusing on the NTD and determining the altered structure in
the context of the fusion partner before assessing the function of specific NTD amino acids and h...

## Key facts

- **NIH application ID:** 10814379
- **Project number:** 5R01CA256161-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adrian V Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,223
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814379

## Citation

> US National Institutes of Health, RePORTER application 10814379, Estrogen receptor fusions genes as drivers of endocrine resistance in breast cancer (5R01CA256161-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814379. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*