HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42[S]

• Published in: The Journal of biological chemistry Vol. 285; no. 38; pp. 29491 - 29501
• Main Authors: Johnson, Emhonta, Seachrist, Darcie D., DeLeon-Rodriguez, Carlos M., Lozada, Kristen L., Miedler, John, Abdul-Karim, Fadi W., Keri, Ruth A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blotting, Western; Breast Cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Catenins - genetics; Catenins - metabolism; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Adhesion; Cell Biology; Cell Line; Cell Line, Tumor; Cell Migration; Cell Movement - genetics; Cell Movement - physiology; Epithelial Cell; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; In Vitro Techniques; Mice; Mice, Nude; Molecular Bases of Disease; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Receptor Tyrosine Kinase; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Src; Tumor Metastases; Wound Healing - genetics; Wound Healing - physiology; Cell Migration; Src; Epithelial Cell; Tumor Metastases; Breast Cancer; Cell Adhesion; Receptor Tyrosine Kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.136770

Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.