# Mechanism-based strategies to target ER-mutant endocrine resistant breast cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $393,861

## Abstract

Project Summary
Two thirds of breast tumors express estrogen receptor (ERα), and although many initially respond to endocrine
therapy, a large fraction subsequently develop resistance, causing death due to advanced hormone-resistant
disease. A number of groups, including ours, have recently documented the occurrence of single nucleotide
mutations in the ERα gene (ESR1) in 20-30% of endocrine-resistant metastatic breast cancer. Limited clinical
evidence suggests that patients whose tumors have gained ESR1 mutations suffer from shorter survival.
ESR1 hotspot mutations cluster in the ligand-binding domain. Analysis of our CRISPR/Cas9 genome edited
breast cancer cells with the most common ESR1 mutations (Y537S and D538G) showed ligand-independent
transcriptional activity, and partial resistance to selective estrogen receptor modulators (SERMs) and
downregulators (SERDs). Mutant ERα also shows regulation of genes not classically regulated by estrogen,
with significant differences between D538G and Y537S. Genes uniquely regulated by mutant ERα are involved
in motility, migration, and adhesion, and we have identified such gain-of-function phenotypes in the ESR1-
mutant cells. We hypothesize that mutations in ESR1 are enriched in endocrine-resistant breast cancer
due to ligand-independent activity of mutant ERα, and a unique gain of function regulating motility and
adhesion. The altered transcriptional activities of mutant ERα are mediated by reprograming of the
ERα cistrome, as a result of altered interaction with coregulators. Finally, we hypothesize that SERDs
will be most effective in inhibiting mutant ERα driven tumor growth.
To address these hypotheses we will use a multidisciplinary approach including unique in vitro and in vivo
models of mutant ERα action, and analysis of clinical specimens. The specific aims are 1) Evaluate how
different ESR1 mutations alter its transcriptional activity and function, 2) Characterize the ligand-dependent
and drug-resistant activities of mutant ERa, focusing on gain of function activities, and 3) Determine whether
the unique transcriptional regulation by mutant ERα is present in advanced endocrine resistant breast cancers,
and whether it is critical for progression and metastasis.
We expect that our comprehensive structure-function studies of ERα mutations will not only provide basic
information regarding hormone resistance, but will highlight novel routes to therapeutic targeting. !

## Key facts

- **NIH application ID:** 9898154
- **Project number:** 5R01CA221303-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Steffi Oesterreich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,861
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898154

## Citation

> US National Institutes of Health, RePORTER application 9898154, Mechanism-based strategies to target ER-mutant endocrine resistant breast cancer (5R01CA221303-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898154. Licensed CC0.

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