# Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $324,901

## Abstract

Our research focus is estrogen receptor (ER)-positive luminal breast cancer, representing 75% of primary breast
cancer patients, who are prescribed adjuvant endocrine therapy (ET) with hormonal agents. While recurrences
are delayed by the use of ET, resistance can evolve with the development of metastatic breast cancer (MBC) in
about one-fourth of ER-positive patients. MBC patients acquire ESR1 mutations in a significant percentage of
cases. Our overall goal is to identify new therapeutic vulnerabilities in ESR1m preclinical models that can
effectively block distant metastatic progression. Our proposal is highly translational. We hypothesize that
acquired ESR1m function as activated “oncogenes” inducing defective replication stress (RS) that suppresses
the DNA damage response (DDR), leading to a metastatic phenotype with actionable targets. Our innovation
includes a unique transplantable ER+ patient derived xenograft (PDX) frozen metastatic tumor bank to explore
the effects of selective cell cycle and DDR inhibitors. In Aim 1 we will study RS and DDR signaling in ex vivo
metastatic organoid cultures, focusing on ATR/Chk1, and PARP inhibitor effects on the DDR and its interactions
with ESR1m. In Aim 2, we will focus on cell cycle proteins AURKA/B and CDK1/2 to arrest the cell cycle in
ESR1m tumors. In Aim 3 we will evaluate mutant metastasis in vivo and the effects of novel therapeutics on
estrogen responses, EMT, and stem cell blockade. It is essential that the discovery of new therapeutic targets
and the preclinical testing of novel approaches be performed using metastatic models. Currently most preclinical
investigators only evaluate primary tumor proliferation, which may not reflect the ability of targeted inhibitors to
block the complex steps of metastasis. We predict that identifying the heterogeneity of driver mechanisms using
experimental modeling of ESR1 mutants will serve an important role in the development of therapeutic
combination interventions to overcome the clinical problem of resistance and rapid tumor progression. Our
project will fill a big gap in our clinical knowledge of how best to treat breast cancer patients who recur with
multiple and heterogeneous ER-positive metastases. With successful completion of our Aims we can impact
the effective ET maintenance of patients with ER-positive MBC and significantly delay time to progression.

## Key facts

- **NIH application ID:** 10755282
- **Project number:** 5R01CA072038-23
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Suzanne AW Fuqua
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $324,901
- **Award type:** 5
- **Project period:** 1996-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755282

## Citation

> US National Institutes of Health, RePORTER application 10755282, Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis (5R01CA072038-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10755282. Licensed CC0.

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