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PMID: 21079779 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Versican G3 promotes mouse mammary tumor cell growth, migration, and metastasis by influencing EGF receptor signaling.

PloS one ·Vol. 5 ·No. 11 ·2010-11-05 ·Pages e13828

Du WW, Yang BB, Shatseva TA, Yang BL, Deng Z, Shan SW, Lee DY, Seth A, Yee AJ

Abstract

Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis.

MeSH Terms
Animals Binding Sites/genetics Blotting, Western Cell Line, Tumor Cell Movement Cell Proliferation Cyclin-Dependent Kinase 2/metabolism Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism Female Gene Expression Regulation, Neoplastic/drug effects Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Mammary Neoplasms, Experimental/genetics,metabolism,pathology Mice Mice, Inbred BALB C Neoplasm Metastasis Neoplasm Transplantation Phosphorylation Reverse Transcriptase Polymerase Chain Reaction Serine/metabolism Signal Transduction Transfection Versicans/genetics,metabolism,physiology
Chemicals
Vcan protein, mouse Versicans Serine Epidermal Growth Factor ErbB Receptors GSK3B protein, human Glycogen Synthase Kinase 3 beta Gsk3b protein, mouse Cdk2 protein, mouse Cyclin-Dependent Kinase 2 Glycogen Synthase Kinase 3
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Du William Weidong
Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Yang Burton B
Shatseva Tatiana A
Yang Bing L
Deng Zhaoqun
Shan Sze Wan
Lee Daniel Y
Seth Arun
Yee Albert J
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0013828
Published
2010-11-05
Epub
2010-00-05
Pages
e13828
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2974650
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0013828 PMC Full Text View journal details
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