title: CTGF enhances the motility of breast cancer cells via an integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway.
abstract: Connective tissue growth factor (CTGF) expression is elevated in advanced stages of breast cancer, but the regulatory role of CTGF in invasive breast cancer cell phenotypes is unclear. Presently, overexpression of CTGF in MCF-7 cells (MCF-7/CTGF cells) enhanced cellular migratory ability and spindle-like morphological alterations, as evidenced by actin polymerization and focal-adhesion-complex aggregation. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) impaired cellular migration and promoted a change to an epithelial-like morphology. A neutralizing antibody against integrin alphavbeta3 significantly attenuated CTGF-mediated ERK1/2 activation and cellular migration, indicating that the integrin-alphavbeta3-ERK1/2 signaling pathway is crucial in mediating CTGF function. Moreover, the cDNA microarray analysis revealed CTGF-mediated regulation of the prometastatic gene S100A4. Transfection of MCF-7/CTGF cells with AS-S100A4 reversed the CTGF-induced cellular migratory ability, whereas overexpression of S100A4 in MDA231/AS cells restored their high migratory ability. Genetic and pharmacological manipulations suggested that the CTGF-mediated S100A4 upregulation was dependent on ERK1/2 activation, with expression levels of CTGF and S100A4 being closely correlated with human breast tumors. We conclude that CTGF plays a crucial role in migratory/invasive processes in human breast cancer by a mechanism involving activation of the integrin-alphavbeta3-ERK1/2-S100A4 pathway.
authors.affiliation: Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, and Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pai-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Wang
authors.forename: Shin-Ni
authors.initials: SN
authors.lastname: Wu
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
authors.forename: Chih-Chen
authors.initials: CC
authors.lastname: Hong
authors.forename: Shuang-En
authors.initials: SE
authors.lastname: Chuang
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Cha
authors.forename: Munisamy Suresh
authors.initials: MS
authors.lastname: Babu
authors.forename: Chiung-Nien
authors.initials: CN
authors.lastname: Chen
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D048430:Cell Shape; D055513:Connective Tissue Growth Factor; D004789:Enzyme Activation; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000199:Actins; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D051419:Paxillin; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D055513:Connective Tissue Growth Factor; C077591:S100A4 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3