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First published online June 5, 2007
doi: 10.1242/10.1242/jcs.03460

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CTGF enhances the motility of breast cancer cells via an integrin-vβ3–ERK1/2-dependent S100A4-upregulated pathway

Pai-Sheng Chen^1,2,*, Ming-Yang Wang^1,2,3,*, Shin-Ni Wu¹, Jen-Liang Su^4,5,6, Chih-Chen Hong⁷, Shuang-En Chuang⁷, Min-Wei Chen¹, Kuo-Tai Hua¹, Yu-Ling Wu¹, Shih-Ting Cha¹, Munisamy Suresh Babu¹, Chiung-Nien Chen^2,3, Po-Huang Lee^2,3, King-Jen Chang^2,3,, and Min-Liang Kuo^1,2,,

¹ Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
² Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan
³ Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
⁴ Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taichung 404, Taiwan
⁵ Center for Molecular Medical, China Medical University Hospital, Taichung 404, Taiwan
⁶ Department of Biotechnology and Bioinformatics, Asia University, Taichung 41354, Taiwan
⁷ Division of Cancer Research, National Health Research Institutes, Taipei 10016, Taiwan

Authors for correspondence (e-mails: kingjen{at}ntu.edu.tw; kuominliang{at}ntu.edu.tw)

Accepted 11 April 2007

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 vβ3 significantly attenuated CTGF-mediated ERK1/2 activation and cellular migration, indicating that the integrin-vβ3–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-vβ3–ERK1/2–S100A4 pathway.

Key words: Connective tissue growth factor, Breast cancer, ERK1/2, Integrin, S100A4, Cell migration, F-actin

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