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Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility.

Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL
J Biol Chem. 2004 279 (23): 24505-13

PMID: 15044465 · DOI:10.1074/jbc.M400081200

We have examined overexpression of the human epidermal growth factor receptor 2 (HER2) to determine if it modifies the anti-proliferative effect of transforming growth factor (TGF)-beta against MCF-10A human mammary epithelial cells. Exogenous TGF-beta inhibited cell proliferation and induced Smad-dependent transcriptional reporter activity in both MCF-10A/HER2 and MCF-10A/vector control cells. Ligand-induced reporter activity was 7-fold higher in HER2-overexpressing cells. In wound closure and transwell assays, TGF-beta induced motility of HER2-transduced, but not control cells. The HER2-blocking antibody trastuzumab (Herceptin) prevented TGF-beta-induced cell motility. Expression of a constitutively active TGF-beta type I receptor (ALK5(T204D)) induced motility of MCF-10A/HER2 but not MCF-10A/vector cells. TGF-beta-induced motility was blocked by coincubation with either the phosphatidylinositol 3-kinase inhibitor LY294002, the mitogen-activated protein kinase (MAPK) inhibitor U0126, the p38 MAPK inhibitor SB202190, and an integrin beta(1) blocking antibody. Rac1 activity was higher in HER2-overexpressing cells, where both Rac1 and Pak1 proteins were constitutively associated with HER2. Both exogenous TGF-beta and transduction with constitutively active ALK5 enhanced this association. TGF-beta induced actin stress fibers as well as lamellipodia within the leading edge of wounds. Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity. These data suggest that 1) overexpression of HER2 in nontumorigenic mammary epithelial is permissive for the ability of TGF-beta to induce cell motility and Rac1 activity, and 2) HER2 and TGF-beta signaling cooperate in the induction of cellular events associated with tumor progression.

MeSH Terms (47)

Actins Activin Receptors, Type I Adenoviridae Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Blotting, Northern Breast Neoplasms Bromodeoxyuridine Butadienes Cell Cycle Cell Division Cell Line Cell Line, Tumor Cell Movement Chromones Disease Progression DNA, Complementary Enzyme Inhibitors Epithelial Cells Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins Humans Imidazoles Immunoblotting Integrin beta1 Ligands Luminescent Proteins Microscopy, Fluorescence Models, Genetic Morpholines Nitriles Phosphoinositide-3 Kinase Inhibitors Precipitin Tests Protein-Serine-Threonine Kinases Pseudopodia Pyridines rac1 GTP-Binding Protein Receptor, ErbB-2 Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta Retroviridae Signal Transduction Transcription, Genetic Transforming Growth Factor beta Trastuzumab Wound Healing

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