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

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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 PRcre/+Ptenf/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.

Original languageEnglish (US)
Pages (from-to)7371-7382
Number of pages12
JournalCancer Research
Volume74
Issue number24
DOIs
StatePublished - Dec 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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