title: Versican G3 promotes mouse mammary tumor cell growth, migration, and metastasis by influencing EGF receptor signaling.
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.
authors.affiliation: Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: William Weidong
authors.initials: WW
authors.lastname: Du
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Shatseva
authors.forename: Bing L
authors.initials: BL
authors.lastname: Yang
authors.forename: Zhaoqun
authors.initials: Z
authors.lastname: Deng
authors.forename: Sze Wan
authors.initials: SW
authors.lastname: Shan
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Lee
authors.forename: Arun
authors.initials: A
authors.lastname: Seth
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Yee
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D053675:Versicans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C508323:Vcan protein, mouse; D053675:Versicans; D012694:Serine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3