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[Cancer Research 63, 140-148, January 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

ERBB2 Up-Regulates S100A4 and Several other Prometastatic Genes in Medulloblastoma1

Roberto Hernan, Rami Fasheh, Christopher Calabrese, Adrian J. Frank, Kirsteen H. Maclean, David Allard, Roger Barraclough and Richard J. Gilbertson2

Departments of Developmental Neurobiology [R. H., R. F., C. C., A. J. F., R. J. G.] and Biochemistry [K. H. M.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, and School of Biological Sciences, Life Sciences Building, University of Liverpool, Liverpool L69 7ZB, United Kingdom [D. A., R. B.]

Medulloblastoma is frequently disseminated throughout the central nervous system by the time of diagnosis. Conventional therapeutic approaches have not reduced the high mortality associated with metastatic medulloblastoma and little is known regarding the molecular mechanisms that promote tumor invasion. Previously, we reported that overexpression of ERBB2 in medulloblastoma is associated with poor prognosis and metastasis. Here, we demonstrate that ERBB2 overexpression increases the migration of medulloblastoma cells across basement membranes in vitro. Furthermore, using microarray expression profiling, we show that ERBB2 up-regulates the expression of prometastatic genes in medulloblastoma cells. These include S100A4, which was previously shown to promote metastasis of breast cancer. We demonstrate that S100A4 is a direct target of ERBB2 signaling in medulloblastoma cells via a pathway involving phosphatidylinositol 3-kinase, AKT1, and extracellular signal-regulated kinase 1/2 and that levels of ERBB2 and S100A4 are tightly correlated in samples of primary medulloblastoma. Finally, we show that ERBB2-dependent medulloblastoma cell invasion in vitro and prometastatic gene expression in vivo can be blocked using the ERBB tyrosine kinase inhibitor OSI-774. These data identify an ERBB2 driven prometastatic pathway that may provide a novel target for therapeutic intervention in metastatic medulloblastoma.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.