Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-like-2

Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, w...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2012-05, Vol.72 (9), p.2440-2453
Main Authors: CIEPLY, Benjamin, RILEY IV, Philip, PIFER, Phillip M, WIDMEYER, Joseph, ADDISON, Joseph B, IVANOV, Alexey V, DENVIR, James, FRISCH, Steven M
Format: Article
Language:English
Subjects:
Anoikis - physiology
Antineoplastic agents
Biological and medical sciences
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
DNA-Binding Proteins - metabolism
Epithelial-Mesenchymal Transition
Homeodomain Proteins - metabolism
Humans
Medical sciences
Pharmacology. Drug treatments
Transcription Factors - metabolism
Transforming Growth Factor beta - metabolism
Tumors
Zinc Finger E-box-Binding Homeobox 1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-11-4038