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