Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. An additional endometrial cancer mouse model is generated by the ablation of phosphatase and tensin homolog deleted from chromosome 10 (Pten)(either as heterozygotes or by conditional uterine ablation). To determine the interplay between Mig-6 and the PTEN/phosphoinositide 3-kinase signaling pathway during endometrial tumorigenesis, we generated mice with Mig-6 and Pten conditionally ablated in progesterone receptor-positive cells (PR cre/+ Mig-6 f/f Pten f/f; Mig-6 d/d Pten d/d). The ablation of both Mig-6 and Pten dramatically accelerated the development of endometrial cancer compared with the single ablation of either gene. The epithelium of Mig-6 d/d Pten d/d mice showed a significant decrease in the number of apoptotic cells compared with Pten d/d mice. The expression of the estrogen-induced apoptotic inhibitors Birc1 was significantly increased in Mig-6 d/d Pten d/d mice. We identified extracellular signal-regulated kinase 2 (ERK2) as an MIG-6 interacting protein by coimmunoprecipitation and demonstrated that the level of ERK2 phosphorylation was increased upon Mig-6 ablation either singly or in combination with Pten ablation. These results suggest that Mig-6 exerts a tumor-suppressor function in endometrial cancer by promoting epithelial cell apoptosis through the downregulation of the estrogen-induced apoptosis inhibitors Birc1 and the inhibition of ERK2 phosphorylation.