# Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $384,945

## Abstract

Project Summary
Uterine fibroids (leiomyomoas) are the most common gynecologic tumor in women of reproductive age. Although
these tumors are considered benign, they cause significant gynecologic and reproductive dysfunction. The
molecular mechanisms that regulate the development and growth of uterine fibroids are not well-understood,
which has resulted in limited, non-invasive therapeutic options. As such, uterine fibroids are the leading indication
for hysterectomy in the United States. There is a critical need for new therapeutic interventions that involve
selectively targeting the pathways that promote fibroid growth. We have recently discovered that activation of
the glucocorticoid receptor (GR) promotes uterine fibroid cell proliferation. Moreover, we found that
glucocorticoids induce a unique transcriptional response in uterine fibroid cells compared to normal myometrium.
Studies in tumors of the breast and endometrium demonstrates that steroid hormone crosstalk allows context-
specific signaling supporting tumor growth and is associated with a poor prognosis. Our preliminary data in the
uterus indicates that GR demonstrates crosstalk with the sex hormone receptors, estrogen (ER) and
progesterone (PR) receptor, known factors that induce uterine fibroid growth. A mechanistic understanding of
glucocorticoid action in the uterus is limited, and thus, glucocorticoid signaling represents a previously
unexplored pathway contributing to the pathogenesis of uterine fibroids. We hypothesize that GR functions as a
critical transcriptional regulatory factor contributing to the pathogenesis of uterine fibroids. We propose to test
our hypotheses in three specific aims. In Specific Aim 1, we will define the mechanisms responsible for the
differential responses to glucocorticoids in uterine fibroids compared to normal myometrial cells. In Specific Aim
2, we will define the molecular mechanism by which GR regulates uterine fibroid cell proliferation. Finally, the
goal of Aim 3 will be to discover how steroid hormone crosstalk regulates gene expression in uterine fibroid cells.
The proposed work is innovative because our studies represent the first investigation into the actions of GR and
the interplay of steroid hormone receptors in uterine fibroid cells. By defining the processes by which
glucocorticoid signaling promotes fibroid cell proliferation, these studies will generate new data to advance our
understanding of this highly prevalent gynecological disease. Successful completion of these studies may open
the door to the development of interventions that selectively target GR regulatory factors or down-stream
signaling molecules of GR for the non-invasive treatment of uterine fibroids.

## Key facts

- **NIH application ID:** 10058465
- **Project number:** 1R01HD100563-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shannon D Whirledge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,945
- **Award type:** 1
- **Project period:** 2020-08-02 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058465

## Citation

> US National Institutes of Health, RePORTER application 10058465, Steroid Receptor Crosstalk and Pathogenesis of Uterine Fibroids (1R01HD100563-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10058465. Licensed CC0.

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