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Aberrant Expression of Cortactin in Head and Neck Squamous Cell Carcinoma Cells Is Associated with Enhanced Cell Proliferation and Resistance to the Epidermal Growth Factor Receptor Inhibitor Gefitinib

Author:
Timpson, P.   Wilson, A. S.   Lehrbach, G. M.   Sutherland, R. L.   Musgrove, E. A.   Daly, R. J.  


Journal:
Cancer Research


Issue Date:
2007


Abstract(summary):

The CTTN gene (formerly designated EMS), encodes cortactin, a key regulator of dynamic actin networks. Both CTTN and CCND1, the latter encoding the cell cycle regulator cyclin D1, reside at chromosomal locus 11q13, a region commonly amplified in breast cancers and head and neck squamous cell carcinoma (HNSCC). Previously, we identified a novel role for cortactin in cancer cells, whereby cortactin overexpression attenuated ligand-induced down-regulation of the epidermal growth factor (EGF) receptor (EGFR), leading to sustained signaling. However, how this affected growth factor-induced cellular responses was unclear. Here, by modulation of cortactin expression in a panel of HNSCC cell lines, we show that cortactin overexpression enhances serum- and EGF_ stimulated proliferation under both anchorage-dependent and anchorage-independent conditions and also increases resistance to anoikis (detachment-induced apoptosis). These effects are associated with increased activation of extracellular signal-regulated kinase and/or AKT. Furthermore, we report that cortactin stabilizes the c-MET receptor tyrosine kinase and enhances hepatocyte growth factor-induced mitogenesis and cell scattering. Therefore, cortactin may modulate signaling by a broader range of receptors than originally proposed and thereby affect a variety of responses. Finally, we have determined that cortactin overexpression, either alone or in combination with cyclin D1 up-regulation, promotes resistance to the EGFR kinase inhibitor gefitinib. These findings indicate that cortactin may play multiple roles in progression of HNSCC and should be evaluated as a marker of prognosis, disease progression, and therapeutic responsiveness, particularly to EGFR-directed agents.


Page:
9304-9314


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