(200) FKBP5 expression is essential for overcoming progesterone resistance in endometrium.

Keun Cheon Kim, Grace Winheim, DaHye Kang, Jae-Wook Jeong and Tae Hoon Kim

Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, MO 65211, USA

Abstract Text:

Progesterone (P4) treatment has been used clinically for the treatment of women’s disease such as endometriosis and endometrial hyperplasia/cancer. However, response rates to P4 therapy vary, and the molecular mechanisms underlying P4 resistance remain poorly understood. P4 resistance refers to a decreased responsiveness to bioavailable P4 and can result from the loss of PGR or its target pathways. A lack of P4 activity contributes to endometrial hyperplasia and cancer progression by allowing unchecked E2-mediated endometrial growth. P4 has been shown to increase the expression of FKBP5, suggesting a role for FKBP5 within the human endometrium, while its downregulation has been observed in human cancers. However, the role of FKBP5 in P4-resistant endometrium remains elusive. In previous studies, we developed mice with the conditional knockout of Mig-6 in all uterine compartments (Pgr^cre/+Mig-6^f/f; Mig-6^KO) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2f^cre/+Mig-6^f/f; Mig-6^Ep-KO) mice. While Mig-6^Ep-KO mice responded to P4 treatment leading to normal uterine function, Mig-6^KO mice exhibited P4 resistance, indicating the creation of the first mouse models that closely mimic P4-resistant and P4-responsive endometrial cancer in women. To determine the role of FKBP5 in P4 resistance, control, Mig-6^KO and Mig-6^Ep-KO mice were treated with either P4 or vehicle for one month. Additionally, we investigated the expression of FKBP5 in ovariectomized control, progesterone receptor knock-out (PRKO), Mig-6^KO, and Mig-6^Ep-KO mice treated with P4 in combination with E2 to determine the ovarian steroid hormone regulation of FKBP5. FKBP5 expression was remarkably increased in control and Mig-6^Ep-KO mice but not in Mig-6^KO mice after P4 treatment. However, the expression of FKBP5 was not detected in Mig-6^KO and PRKO mice after P4 treatment for 6 hours. Moreover, control and Mig-6^Ep-KO mice showed higher expression of FKBP5 after P4 with E2 treatment compared with vehicle-treated control and Mig-6^Ep-KO mice. However, FKBP5 expression was not observed in Mig-6^KO mice after P4 with E2 treatment. Our finding confirmed that FKBP5 expression is regulated by P4 and that FKBP5 is target of PGR in our preclinical mouse model, consistent with observation in humans. Furthermore, these results suggest that FKBP5 plays an important role in mediating P4 response in endometrium.

Research supported by NIH R01HD112332 (to T.H.K)