# Gene X Environment Interactions in the Pathogenesis of Uterine Fibroids

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $152,953

## Abstract

Abstract
Uterine Fibroids (UFs) are monoclonal tumors arising in the myometrium, and are the most
common tumor of reproductive age women. An increasing body of evidence supports the
hypothesis that UFs originate from aberrant stem cells in the myometrium. We have now identified
a Stro-1+/CD44+ myometrial stem cell (MSC) capable of self-renewal and regeneration of
myometrial tissues, which gives rise to UFs in animal models. With our ability to identify and
isolate these MSCs, we are in a unique position to address how risk factors impact the UF
cell-of-origin to initiate and promote the development of these tumors.
Like many diseases, there is ample evidence that both environmental exposures and genetic
alterations contribute to UF pathogenesis. We, and others have shown that early life
environmental exposures to endocrine disrupting compounds (EDCs) increase UF risk by
inducing developmental reprogramming of the epigenome. Such epigenomic reprogramming
involves changes in histone and DNA methylation patterns that alter chromatin architecture and
gene transcription, and when induced in early life, persist into adulthood. Genetic alterations in
mediator 12 (MED12) and the tuberous sclerosis complex 2 (TSC2) tumor suppressor, drive
development of UF tumors in both humans and rodent models, respectively. Interestingly, MED12
and TSC2 defects share a common downstream effector: activation of β-catenin signaling and
TCF/LEF transactivation of gene expression.
Our previous inability to interrogate the cells-of-origin for UFs has limited our understanding of
how gene:environment interactions (GxE) influence UF risk. Now that we can isolate and profile
MSCs, we are for the first time in a position to overcome this critical barrier to understanding
determinants of risk for this important disease. In this application we will utilize our new-found
ability to isolate and interrogate MSCs, and apply recent insights on how environmental
exposures reprogram the epigenome, to explore GxE interactions that promote
tumorigenesis in the cell-of-origin for UFs.
Specific Aim 1: Test the hypothesis that activation of β-catenin signaling is a common
effector pathway for genetic alterations that drive UFs. In this mechanistic Aim, we will test
the hypothesis that in MSCs, MED12 mutation (human) or loss of Tsc2 (rat) results in an altered
transcriptional profile characterized by increased TCF/LEF transactivation of gene expression.
Specific Aim 2: Test the hypothesis that developmental EDC exposure results in epigenetic
reprogramming that cooperates with genetic defects in MSC/TICs. In this mechanistic Aim,
we will characterize EDC-induced reprogramming of the epigenome, and test the hypothesis that
reprogramming of TCF/LEF target genes exacerbates their expression when β-catenin is
activated in rMSCs and in tumor initiating cells (TICs).
Specific Aim 3: Test the hypothesis that MSCs associated with high vs low UF risk exhibit
differences in epigenetic histone modificati...

## Key facts

- **NIH application ID:** 9976526
- **Project number:** 5R01ES028615-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Ayman Al-Hendy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $152,953
- **Award type:** 5
- **Project period:** 2017-09-15 → 2020-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976526

## Citation

> US National Institutes of Health, RePORTER application 9976526, Gene X Environment Interactions in the Pathogenesis of Uterine Fibroids (5R01ES028615-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976526. Licensed CC0.

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