# TRANSCRIPTIONAL REPROGRAMMING OF ESR1 MUTANT BREAST CANCER IN METASTASIS AND TREATMENT RESISTANCE

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

Project Summary
Up to 1 in 8 women in the United States will develop invasive breast cancer in their lifetime, with 70-80% of cases
being estrogen receptor positive (ER+). These cancers rely on hormonal signaling, allowing for treatment with
endocrine therapy (ET), including inhibitors of the aromatase enzyme, lowering estrogen levels, or targeting of
the ER itself using modulators and degraders. While these therapies reduce mortality by up to 40%, the disease
often recurs and progresses to metastasis as a result of ET resistance. The main mechanism of resistance is
the acquisition of estrogen receptor gene (ESR1) mutations. These mutations confer constitutive activation to
ER, exhibiting reduced sensitivity to endocrine therapies, and are found in up to 38% of metastases. There is
currently no approved therapy specific to patients harboring these mutations, which should be a clinical priority
given their prevalence in metastatic disease. The Fuqua laboratory has identified distinct transcriptional changes
between primary and metastatic site tumors, and between therapy-resistant ESR1 mutants and wild type ER
cells. In a study of 900 metastatic breast cancer patients, ESR1 mutations were mutually exclusive with other
ER+ breast cancer mutations including Myc and MAPK pathways at the DNA level, but current data in the Fuqua
laboratory and others indicates ESR1 mutations activate these same growth and proliferation pathways at the
transcriptional level. Given the ESR1 mutant’s proclivity for metastasis and therapy-resistance, this proposal’s
central hypothesis is ESR1 mutations generate a transcriptionally reprogrammed phenotype promoting
both metastasis and ET resistance in breast cancer. The rationale for this proposal is that identifying
transcriptional changes in ESR1 metastases and resistant tumors, improves understanding of ESR1 mutant
disease evolution. By targeting transcriptional changes occurring during this evolution, patients can remain on
ET longer and extend metastasis-free survival. To test this central hypothesis, we propose two Specific Aims.
Aim 1: What clonal and transcriptional changes accompany metastasis in ESR1 mutant-containing tumors
subjected to ET pressure? This Aim uses computational methods to identify clonal evolution and transcriptional
drivers of metastasis using single cell RNA/DNA-seq and ChIP-seq. Transcriptional drivers will be validated using
FDA-approved inhibitors of these candidates in combination with ET using ex vivo assays. Aim 2: Does ET
enhance the acquisition of ESR1 mutations, promoting subclonal evolution to drive therapy resistance? This Aim
is addressed by developing models with ESR1 mutations acquired during long-term ET and utilizing
computational biology via a combination of single cell DNA-seq and RNA-seq to determine the clonal evolution
and transcriptional driver candidates of ET resistance. Driver candidates will be validated using selective
inhibitors in combination with ET in vitro and in vi...

## Key facts

- **NIH application ID:** 10370318
- **Project number:** 5F31CA260983-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** SARAH HERZOG
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370318

## Citation

> US National Institutes of Health, RePORTER application 10370318, TRANSCRIPTIONAL REPROGRAMMING OF ESR1 MUTANT BREAST CANCER IN METASTASIS AND TREATMENT RESISTANCE (5F31CA260983-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370318. Licensed CC0.

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