title: Bone sialoprotein stimulates focal adhesion-related signaling pathways: role in migration and survival of breast and prostate cancer cells.
abstract: Bone sialoprotein (BSP) is a secreted glycoprotein found in mineralized tissues however, BSP is aberrantly expressed in a variety of osteotropic tumors. Elevated BSP expression in breast and prostate primary carcinomas is directly correlated with increased bone metastases and tumor progression. In this study, the intracellular signaling pathways responsible for BSP-induced migration and tumor survival were examined in breast and prostate cancer cells (MDA-MB-231, Hs578T and PC3). Additionally, the effects of exogenous TGF-beta1 and EGF, cytokines associated with tumor metastasis and present in high-levels in the bone microenvironment, were examined in BSP-expressing cancer cells. Expression of BSP but not an integrin-binding mutant (BSP-KAE) in tumor cell lines resulted in increased levels of alpha(v)-containing integrins and number of mature focal adhesions. Adhesion of cells to recombinant BSP or the expression of BSP stimulated focal adhesion kinase and ERK phosphorylation, as well as activated AP-1-family proteins. Activation of these pathways by BSP expression increased the expression of the matrix metalloproteinases MMP-2, MMP-9, and MMP-14. The BSP-mediated activation of the FAK-associated pathway resulted in increased cancer cell invasion in a Matrigel-coated Boyden-chamber assay and increased cell survival upon withdrawal of serum. Addition of EGF or TGF-beta1 to the BSP-expressing cell lines significantly increased ERK phosphorylation, AP-1 activation, MMP-2 expression, cell migration and survival compared to untreated cells expressing BSP. This study thus defines the cooperative mechanisms by which BSP can enhance specific factors associated with a metastatic phenotype in tumor cell lines, an effect that is increased by circulating TGF-beta1 and EGF.
authors.affiliation: CIHR Group in Skeletal Development and Remodeling, Department of Biochemistry and Division of Oral Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jonathan A R
authors.initials: JA
authors.lastname: Gordon
authors.forename: Jaro
authors.initials: J
authors.lastname: Sodek
authors.forename: Graeme K
authors.initials: GK
authors.lastname: Hunter
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Goldberg
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D022001:Focal Adhesions; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D008297:Male; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D012795:Sialoglycoproteins / Q000502:physiology*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D012795:Sialoglycoproteins; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor