ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma.
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.
Hernan
Roberto
R
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Fasheh
Rami
R
Calabrese
Christopher
C
Frank
Adrian J
AJ
Maclean
Kirsteen H
KH
Allard
David
D
Barraclough
Roger
R
Gilbertson
Richard J
RJ
D000818:Animals; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018734:Genes, erbB-2; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D008156:Luciferases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C077591:S100A4 protein, human