title: MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer.
abstract: Epithelial-mesenchymal transition (EMT) is one of the decisive steps regulating cancer invasion and metastasis. However, the molecular mechanisms underlying this transition require further clarification. MDA-9/syntenin (SDCBP) expression is elevated in breast cancer patient samples as well as cultured breast cancer cells. Silencing expression of MDA-9 in mesenchymal metastatic breast cancer cells triggered a change in cell morphology in both 2D- and 3D-cultures to a more epithelial-like phenotype, along with changes in EMT markers, cytoskeletal rearrangement and decreased invasion. Conversely, over expressing MDA-9 in epithelial non-metastatic breast cancer cells instigated a change in morphology to a more mesenchymal phenotype with corresponding changes in EMT markers, cytoskeletal rearrangement and an increase in invasion. We also found that MDA-9 upregulated active levels of known modulators of EMT, the small GTPases RhoA and Cdc42, via TGFβ1. Reintroducing TGFβ1 in MDA-9 silenced cells restored active RhoA and cdc42 levels, modulated cytoskeletal rearrangement and increased invasion. We further determined that MDA-9 interacts with TGFβ1 via its PDZ1 domain. Finally, in vivo studies demonstrated that silencing the expression of MDA-9 resulted in decreased lung metastasis and TGFβ1 re-expression partially restored lung metastases. Our findings provide evidence for the relevance of MDA-9 in mediating EMT in breast cancer and support the potential of MDA-9 as a therapeutic target against metastatic disease.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D008841:Actin Cytoskeleton / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D015398:Signal Transduction; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C109621:SDCBP protein, human; D053676:Syntenins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C066737:RHOA protein, human; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: breast cancer; epithelial-mesenchymal transition; melanoma differentiation associated gene-9/syntenin; transforming growth factor beta 1