# Exploring the role of ER Beta in disease penetrance in individuals with Li-Fraumeni syndrome

> **NIH NIH R21** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2022 · $223,282

## Abstract

Abstarct
Individuals with Li-Fraumeni syndrome (LFS) are predisposed to a wide spectrum of cancer types at a relatively
early age. Despite that LFS is linked to germline mutations of p53, these aberrations alone cannot explain the
complex phenotype of the syndrome. The observation that female mutation carriers have higher cancer risk than
males points to a role of sex steroid signaling in affecting disease penetrance. Further, breast cancer whose
etiology relates to aberrant hormonal signaling is the most common malignancy in LFS. However, the effects of
irregular hormone signaling on breast tumorigenesis in LFS have not been explored. Estrogen is essential for
proper development and function of breast tissue. It regulates proliferation and differentiation of epithelial cells
in adolescence and pregnancy. Because cells in development are susceptible to malignant transformation, it is
well accepted that the proliferative action of estrogen is coordinated with an increase in genome surveillance.
Two receptors (ERα and ERβ) mediate the effects of estrogen in mammary tissue. While ERα is responsible for
the proliferative activity of the hormone, ERβ promotes differentiation and regulates DNA damage response
which let us to propose that this subtype is employed by estrogen to ensure genome integrity. In support of this
role, our findings demonstrate that ERβ enhances the activity of p53 in response to genotoxic stress and loss of
synergistic tumor suppressor function as a result of combined inactivation in mammary gland results in early-
onset breast tumors in mice. In addition to wild-type form, we have seen that ERβ binds to mutant p53 to inhibit
its oncogenic function. Since LFS tissues are often heterozygous for mutant p53, we hypothesize that ERβ
coordinates with both alleles of p53 and other pathways to maintain genome stability and, therefore,
dysregulation of ERβ signaling in LFS mammary tissue results in malignant transformation and increased
incidence of breast cancer. Our proposed research will: 1) investigate whether ERβ affects breast tumorigenesis
in LFS, 2) determine effects of ERβ agonists on penetrance in LFS and 3) elucidate the mechanism of ERβ
action. To test whether abnormal ERβ signaling affects breast cancer in LFS, we will analyze virgin and pregnant
mice with germline point p53 mutations that mimic human LFS phenotypes and ubiquitous and mammary gland-
specific inactivation of ERβ. We will also assess ERβ expression in human LFS tissues and identify associations
with the age of tumor onset (Aim 1). In addition, we will treat LFS mice with ERβ agonists that are in clinical trials
for other diseases expecting these compounds to potentiate its tumor suppressor activity and prevent breast
cancer and its associated mortality (Aim 2). Further, we will delineate the mechanisms of ERβ action by analyzing
LFS tissues for pathways that are associated with the phenotype of the syndrome (Aim 3). Determining the
effects of estrogen signali...

## Key facts

- **NIH application ID:** 10613753
- **Project number:** 7R21CA267386-02
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Christoforos Thomas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $223,282
- **Award type:** 7
- **Project period:** 2022-01-10 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10613753

## Citation

> US National Institutes of Health, RePORTER application 10613753, Exploring the role of ER Beta in disease penetrance in individuals with Li-Fraumeni syndrome (7R21CA267386-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10613753. Licensed CC0.

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