Overexpression Mig-6Retards Endometrial Cancer Progression in Conditional Uterine Ablation of Pten.

Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer and alterations in the expression of PTEN have been associated with this disease. Ablation of Mig-6in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. To investigate the impact of overexpression of Mig-6in endometrial cancer development and progression, we have generated mice with conditionally overexpression of Mig-6in the uterus. The elevated expression of Mig-6is accomplished by placing the coding region of Mig-6under the control of a ubiquitously expressed promoter, the chicken beta actin-cytomegalovirus hybrid (CAGGS) promoter. The construction also contained the "Stop Cassette" flanked by LoxP sites (LSL). In order to ensure uniform expression in mice, the CAGGS-LSL-Mig-6transgene is inserted into the ROSA26 locus. In order to investigate the effects of the Mig-6and the PTEN/PI3K/AKT signaling pathways on uterine tumorigenesis, mice with Ptenfloxed (Ptenf/f) and LoxP-STOP-LoxP Mig-6 (R26Mig-6LSL) were bred to the PRCremouse model to generate ablation of Ptenand overexpression of Mig-6in the uterus (PRcre+R26Mig-6LSLPtenf/f). PRcre+R26Mig-6LSLPtenf/fmice showed significantly decreased uterine weight compared to PRcre/+Ptenf/fat 3 months of age. Gross morphology at 3 months of age showed that double mutant mice dramatically retarded the development of endometrial cancer compared to ablation of Pten gene. Histological analysis showed that endometrial adenocarcinoma with invasion into the myometrium was observed in the PRcre/+Ptenf/fmice at 3 months of age. However, double mutant mice did not develop endometrial cancer. Therefore, Mig-6exerts a tumor suppressor function in endometrial cancer. These results will contribute to the understanding of the molecular mechanism of tumorigenesis and to the development of therapeutic approaches for endometrial cancer.(platform)