# Unravelling mechanisms and novel therapeutic targets for progesterone-resistant endometrial hyperplasia

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $454,306

## Abstract

Project Summary
Endometrial hyperplasia is a precursor to endometrial cancer (EC). Complex atypical hyperplasia (CAH) is the
common type of endometrial hyperplasia that becomes EC in 52% of cases if not treated.
Most women with CAH
can be cured by
hysterectomy,
the surgical removal of the uterus.
However, there is an increasing demand for
fertility-sparing treatments for CAH and EC, especially for reproductive-aged women who wish to maintain
fertility. Twenty to thirty percent of the young women with CAH and EC might be eligible for a fertility sparing
approach. Developing fertility-sparing treatments to cure CAH and EC without sacrificing fertility remains an
essential goal in CAH and EC medicine. Poor understanding of the mechanism of progesterone (P4) resistance
in CAH and EC is a major barrier to developing fertility-sparing treatment. P4 is widely used to treat various
gynecological conditions due to its clear antiproliferative effects on E2-mediated endometrial proliferation.
P4, the gold standard of nonsurgical treatment, is often an effective CAH and EC treatment. However, the
response rates to P4 therapy vary and molecular mechanisms behind de novo or acquired P4 resistance are
poorly understood. To increase success rates of P4 therapy as a fertility-sparing treatment, revealing the
mechanisms underlying P4 resistance in CAH and EC and finding biomarkers for P4 responsiveness in human
CAH and EC are critical. The mitogen-inducible gene 6 (MIG-6) is a key P4 signaling mediator in the human and
mouse uterus. Preliminary results show that P4-responsive (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) and P4-resistant
(Pgrcre/+Mig-6f/f; Mig-6KO) mouse models develop CAH via aberrant phosphorylation of AKT and ERK in
endometrial epithelial cells. In P4-responsive mice, P4 controls CAH, restores uterine receptivity, and preserves
fertility. In P4-resistant mice, P4 fails to control CAH, fails to restore uterine receptivity, and fails to preserve
fertility. These data suggest the hypothesis that Mig-6 loss causes P4-resistant CAH by activating AKT signaling
in endometrial epithelial cells and by dysregulating P4 signaling in endometrial stromal and epithelial cells. This
project will investigate the mechanism of P4-resistance by: 1) dissecting the role of MIG-6 in the interaction
between AKT and PGR signaling in endometrial epithelial cells; 2) studying the function of stromal MIG-6 in
response to P4; 3) testing whether combination therapy of P4 + AKT or mTOR inhibition can treat P4-resistant
CAH and restore endometrial function, including fertility; and 4) conducting bioinformatic analysis study that
will identify the transcriptional regulatory function of PGR and find the biomarkers in P4 resistance. This work
will lead to translational outcomes including the development of new therapeutic approaches for fertility-sparing
treatment as well as discovery of new biomarkers, which are important for Precision Medicine in infertility.

## Key facts

- **NIH application ID:** 10899574
- **Project number:** 5R01HD112332-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Tae Hoon Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $454,306
- **Award type:** 5
- **Project period:** 2023-08-04 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899574

## Citation

> US National Institutes of Health, RePORTER application 10899574, Unravelling mechanisms and novel therapeutic targets for progesterone-resistant endometrial hyperplasia (5R01HD112332-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899574. Licensed CC0.

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