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MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT

 Jung-Yoon Yoo  ;  Hee-Bum Kang  ;  Russell R. Broaddus  ;  John I. Risinger  ;  Kyung-Chul Choi  ;  Tae Hoon Kim 
 BMC Cancer, Vol.18(1) : e605, 2018 
Journal Title
 BMC Cancer 
Issue Date
AKT ; Endometrial hyperplasia ; MIG-6 ; Progesterone resistance
BACKGROUND: Aberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells. METHOD: To further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f cre+ Mig-6 f/f ). We examined P4 effect and regulation of AKT signaling in the endometrium of mutant mice. RESULTS: Sprr2f cre+ Mig-6 f/f mice developed endometrial hyperplasia. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling and the restoration of stromal PGR and ESR1 expression. Furthermore, our in vitro studies revealed an inhibitory effect of MIG-6 on AKT phosphorylation as well as MIG-6 and AKT protein interactions. CONCLUSIONS: These data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.
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Yonsei Authors
Yoo, Jung Yoon(유정윤) ORCID logo https://orcid.org/0000-0001-9366-3863
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