title: 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.
abstract: The CTTN gene (formerly designated EMS1), 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.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: Ashleigh S
authors.initials: AS
authors.lastname: Wilson
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Lehrbach
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
mesh_terms: D023102:Anoikis / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002880:Chromosomes, Human, Pair 11; D051356:Cortactin / Q000096:biosynthesis*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D005784:Gene Amplification; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; C495868:CTTN protein, human; D051356:Cortactin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib