Endometrial cancer is the most common cancer of the female reproductive system. PTEN is mutated or absent in more than half of human endometrial cancers. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. Mig-6 suppresses estrogen signaling. Here, we show the significance of MIG-6 in human endometrial cancer through sample analysis, where MIG-6 expression is inversely associated with ERK phosphorylation; this relationship is tightly correlated with endometrial cancer progression. To determine the tumor suppressor function of Mig-6 in the development of endometrial cancer, we generated Mig-6 conditional overexpression mice (R26Mig-6LSL). To assess the effects of Mig-6 on the PTEN/PI3K/AKT signaling pathway in uterine tumorigenesis, mice with Pten floxed (Ptenf/f) and R26Mig-6LSL were bred to the PRCre mouse model to generate overexpression of Mig-6 and ablation of Pten in the uterus (PRcre/+ R26Mig-6LSL Ptenf/f). PRcre/+ R26Mig-6LSL Ptenf/f showed significantly increased survival time and uterine weight compared to PRcre/+ Ptenf/f mice. Gross morphology and histological analysis displayed dramatically suppressed development of endometrial cancer in double mutant mice compared to ablation of Pten alone. Immunohistochemical analysis showed significantly increased apoptosis and decreased proliferation in epithelial cells of PRcre/+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice. Interestingly, the expression of pERK1/2 was significantly decreased in PRcre/+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice. To examine whether inhibition of ERK phosphorylation suppresses tumor progression in endometrial cancer, PRcre/+Ptenf/f mice were treated with U0126, an effective inhibitor of MAPK/ERK kinase. PRcre/+Ptenf/f mice treated with U0126 exhibited a significant reduction in uterine weight. Histopathological analysis of the entire animal cohort showed that inhibition of ERK phosphorylation suppressed endometrial cancer progression in PRcre/+ Ptenf/f mice, as reflected by the arrest of tumors at the hyperplastic or normal stage, whereas tumors from PRcre/+Ptenf/f mice treated with vehicle advanced to endometrial cancer. These results demonstrate that activation of ERK signaling is critical for endometrial cancer development and progression in Pten mutation. Our findings highlight a crucial tumor suppressor role for MIG-6 in progression of PTEN-null endometrial cancer by inhibiting ERK phosphorylation. As MIG-6 is a mediator of progesterone signaling, the activity of which can suppress unopposed-estrogen signaling, our studies provide a potential new drug target for the intervention of metastatic human endometrial cancer.
(This work was supported by NIH, U54 HD007495 to J.P.L, NIH, R01 HD057873 and American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.)
Citation Format: Jung-Yoon Yoo, Tae Hoon Kim, Hong Im Kim, Jane Li, Gordon B. Mills, Russell R. Broaddus, John P. Lydon, Ho-Geun Yoon, Jae-Wook Jeong. Mig-6 suppresses development and progression of endometrial cancer by inhibiting ERK2 phosphorylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 60. doi:10.1158/1538-7445.AM2014-60