# Mechanisms of tamoxifen-associated endometrial cancer risk

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $170,988

## Abstract

PROJECT SUMMARY
Tamoxifen is the most prescribed cancer drug in the world. Tamoxifen is a selective estrogen receptor
modulator (SERM) that is used to treat patients with breast tumors that express estrogen receptor alpha (ER),
acting as a partial antagonist that blocks ER’s growth-promoting activity. The use of tamoxifen has greatly
benefited breast cancer patients by significantly reducing the risk of recurrence. Unfortunately, several severe
side effects accompany the recommended 5-10-year course of tamoxifen treatment, including increased risk of
endometrial cancer. It has been shown that tamoxifen acts as an ER agonist in the endometrium and in
endometrial cancer cells. However, despite the initial observation of tamoxifen-associated endometrial cancer
more than 30 years ago, the molecular mechanisms remain poorly understood. The leading hypothesis is that
different cofactors interact with ER upon tamoxifen binding and these cofactors differ between breast cancer
cells and endometrial cells. In this proposal, we will address the decades-old question of how tamoxifen acts
as an agonist in endometrial cells using cutting edge techniques. We will use two approaches to determine key
factors that underlie tamoxifen’s differential actions in breast and endometrial cancer. In specific aim 1, we will
focus on the cofactor hypothesis by applying RIME, which identifies co-occurring factors on chromatin, to
breast cancer cells and our unique collection of endometrial cancer and normal endometrial samples that have
undergone treatment with estradiol and 4-hydroxytamoxifen. In specific aim 2, we will cast a broader net by
using CRISPR approaches to identify genes essential for tamoxifen’s ER agonist role in endometrial cells and
compare results to similar studies in breast cancer cells. The successful completion of this project will lead to a
mechanistic understanding of how tamoxifen has dichotomous roles, being both an effective breast cancer
treatment and an endometrial cancer risk factor. This knowledge will aid in identifying alternative breast cancer
treatment strategies that reduce the chance of developing a deadly side effect and will help in discovering new
therapeutic targets for endometrial cancer patients.

## Key facts

- **NIH application ID:** 10815809
- **Project number:** 5R21CA270580-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jason Gertz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,988
- **Award type:** 5
- **Project period:** 2023-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815809

## Citation

> US National Institutes of Health, RePORTER application 10815809, Mechanisms of tamoxifen-associated endometrial cancer risk (5R21CA270580-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815809. Licensed CC0.

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