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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.    Electronic supplementary material  The online version of this article (10.1186/s12885-018-4502-7) contains supplementary material, which is available to authorized users.

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