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 Mills, Russell R. Broaddus, John P. Lydon, Jeong Mook Lim, Ho Geun Yoon, Jae Wook Jeong

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

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Endometrial Neoplasms
Neoplasms
Carcinogenesis
Phosphorylation
Progesterone Receptors
Estrogen Receptors
Transgenic Mice
Progesterone
Estrogens
Epithelial Cells
Steroids
Cell Proliferation
Hormones
Apoptosis
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kim, T. H., Yoo, J. Y., Kim, H. I., Gilbert, J., Ku, B. J., Li, J., ... Jeong, J. W. (2014). Mig-6 suppresses endometrial cancer associated with pten deficiency and ERK activation. Cancer Research, 74(24), 7371-7382. https://doi.org/10.1158/0008-5472.CAN-14-0794

Mig-6 suppresses endometrial cancer associated with pten deficiency and ERK activation. / Kim, Tae Hoon; Yoo, Jung Yoon; Kim, Hong Im; Gilbert, Jenifer; Ku, Bon Jeong; Li, Jane; Mills, Gordon; Broaddus, Russell R.; Lydon, John P.; Lim, Jeong Mook; Yoon, Ho Geun; Jeong, Jae Wook.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7371-7382.

Research output: Contribution to journalArticle

Kim, TH, Yoo, JY, Kim, HI, Gilbert, J, Ku, BJ, Li, J, Mills, G, Broaddus, RR, Lydon, JP, Lim, JM, Yoon, HG & Jeong, JW 2014, 'Mig-6 suppresses endometrial cancer associated with pten deficiency and ERK activation', Cancer Research, vol. 74, no. 24, pp. 7371-7382. https://doi.org/10.1158/0008-5472.CAN-14-0794
Kim, Tae Hoon ; Yoo, Jung Yoon ; Kim, Hong Im ; Gilbert, Jenifer ; Ku, Bon Jeong ; Li, Jane ; Mills, Gordon ; Broaddus, Russell R. ; Lydon, John P. ; Lim, Jeong Mook ; Yoon, Ho Geun ; Jeong, Jae Wook. / Mig-6 suppresses endometrial cancer associated with pten deficiency and ERK activation. In: Cancer Research. 2014 ; Vol. 74, No. 24. pp. 7371-7382.
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