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Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation

Authors
 Tae Hoon Kim  ;  Jung-Yoon Yoo  ;  Hong Im Kim  ;  Jenifer Gilbert  ;  Bon Jeong Ku  ;  Jane Li  ;  Gordon B. Mills  ;  Russell R. Broaddus  ;  John P. Lydon  ;  Jeong Mook Lim  ;  Ho Geun Yoon  ;  Jae-Wook Jeong 
Citation
 CANCER RESEARCH, Vol.74(24) : 7371-7382, 2014 
Journal Title
 CANCER RESEARCH 
ISSN
 0008-5472 
Issue Date
2014
MeSH
Animals ; Apoptosis/genetics ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/genetics ; Endometrial Neoplasms/genetics* ; Endometrial Neoplasms/metabolism ; Endometrial Neoplasms/pathology ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/biosynthesis ; Intracellular Signaling Peptides and Proteins/genetics* ; MAP Kinase Signaling System/genetics ; Mice ; Mice, Transgenic ; PTEN Phosphohydrolase/deficiency ; PTEN Phosphohydrolase/genetics* ; Phosphorylation ; Transcriptional Activation*
Abstract
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.
Full Text
http://cancerres.aacrjournals.org/content/74/24/7371
DOI
10.1158/0008-5472.CAN-14-0794
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/138414
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