Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation.
PTEN mutations are the most common genetic alterations in endometrial cancer. Loss of PTEN and subsequent AKT activation stimulate estrogen receptor α-dependent pathways that play an important role in endometrial tumorigenesis. The major pathologic phenomenon of endometrial cancer is the loss of ovarian steroid hormone control over uterine epithelial cell proliferation and apoptosis. However, the precise mechanism of PTEN/AKT signaling in endometrial cancer remains poorly understood. The progesterone signaling mediator MIG-6 suppresses estrogen signaling and it has been implicated previously as a tumor suppressor in endometrial cancer. In this study, we show that MIG-6 also acts as a tumor suppressor in endometrial cancers associated with PTEN deficiency. Transgenic mice, where Mig-6 was overexpressed in progesterone receptor-expressing cells, exhibited a relative reduction in uterine tumorigenesis caused by Pten deficiency. ERK1/2 was phosphorylated in uterine tumors and administration of an ERK1/2 inhibitor suppressed cancer progression in PR(cre/+)Pten(f/f) mice. In clinical specimens of endometrial cancer, MIG-6 expression correlated inversely with ERK1/2 phosphorylation during progression. Taken together, our findings suggest that Mig-6 regulates ERK1/2 phosphorylation and that it is crucial for progression of PTEN-mutant endometrial cancers, providing a mechanistic rationale for the evaluation of ERK1/2 inhibitors as a therapeutic treatment in human endometrial cancer.
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan.
Tae Hoon
TH
Kim
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan. Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medicine Science, Yonsei University College of Medicine, Seoul, South Korea.
Jung-Yoon
JY
Yoo
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan.
Hong Im
HI
Kim
Institute of Immunology, National University of Ireland, Maynooth, Ireland.
Jenifer
J
Gilbert
Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
Bon Jeong
BJ
Ku
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jane
J
Li
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Gordon B
GB
Mills
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Russell R
RR
Broaddus
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
John P
JP
Lydon
Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.
Jeong Mook
JM
Lim
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medicine Science, Yonsei University College of Medicine, Seoul, South Korea. JaeWook.Jeong@hc.msu.edu yhgeun@yuhs.ac.
Ho-Geun
HG
Yoon
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, Michigan. JaeWook.Jeong@hc.msu.edu yhgeun@yuhs.ac.
Jae-Wook
JW
Jeong
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D015533:Transcriptional Activation
C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse