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BMC Cancer. 2012; 12: 82.
Published online Mar 7, 2012. doi:  10.1186/1471-2407-12-82
PMCID: PMC3372425
Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells
Hannah Mak,#1 Alexandra Naba,#2,4 Sonal Varma,#3 Colleen Schick,1 Andrew Day,3 Sandip K SenGupta,3 Monique Arpin,2 and Bruce E Elliottcorresponding author1
1Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada
2Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR (Unité Mixte de Recherche) 144 CNRS (Centre National de la Recherche Scientifique), Institut Curie, Paris, France
3Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L3N6, Canada
4Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
corresponding authorCorresponding author.
#Contributed equally.
Hannah Mak: hannah.y.mak/at/gmail.com; Alexandra Naba: anaba/at/mit.edu; Sonal Varma: dr.sonal.varma/at/gmail.com; Colleen Schick: schickc/at/queensu.ca; Andrew Day: daya/at/KGH.KARI.NET; Sandip K SenGupta: sengupts/at/KGH.KARI.NET; Monique Arpin: monique.arpin/at/curie.fr; Bruce E Elliott: elliottb/at/queensu.ca
Received August 31, 2011; Accepted March 7, 2012.
Abstract
Background
The membrane cytoskeletal crosslinker, ezrin, a member of the ERM family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. Our group previously showed that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in deregulation of cell-cell contacts and scattering of epithelial cells. In particular, ezrin phosphorylation on Y477 by Src is specific to ezrin within the ERM family, and is required for HGF-induced scattering of epithelial cells. We therefore sought to examine the role of Y477 phosphorylation in ezrin on tumor progression.
Methods
Using a highly metastatic mouse mammary carcinoma cell line (AC2M2), we tested the effect of over-expressing a non-phosphorylatable form of ezrin (Y477F) on invasive colony growth in 3-dimensional Matrigel cultures, and on local invasion and metastasis in an orthotopic engraftment model.
Results
AC2M2 cells over-expressing Y477F ezrin exhibited delayed migration in vitro, and cohesive round colonies in 3-dimensional Matrigel cultures, compared to control cells that formed invasive colonies with branching chains of cells and numerous actin-rich protrusions. Moreover, over-expression of Y477F ezrin inhibits local tumor invasion in vivo. Whereas orthotopically injected wild type AC2M2 tumor cells were found to infiltrate into the abdominal wall and visceral organs within three weeks, tumors expressing Y477F ezrin remained circumscribed, with little invasion into the surrounding stroma and abdominal wall. Additionally, Y477F ezrin reduces the number of lung metastatic lesions.
Conclusions
Our study implicates a role of Y477 ezrin, which is phosphorylated by Src, in regulating local invasion and metastasis of breast carcinoma cells, and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic/predictive marker or treatment target for invasive human breast cancer.
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