ROLE OF CORTACTIN IN HEAD AND NECK CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cortactin is a cortical actin-binding protein and substrate for various tumor-promoting oncogenic kinases. Cortactin also interacts with the actin-related (Arp) 2/3 protein complex, which drives cell motility by initiating and maintaining polymerization of actin filaments at the leading edge of motile cells. Arp2/3 activation is critical for the formation of lamellipodia, the initial step involved in cell migration. Lamellipodia also play a major role in tumor cell invasion, allowing cancer cells to invade and spread into adjacent tissues. Cortactin is overexpressed in several human cancers, most frequently in head and neck squamous cell carcinoma (HNSCC) as a result of amplification of the chromosome 11q13 region. HNSCC is the most common cancer that afflicts the oral cavity and associated tissues, and follows a well-defined paradigm of tumor progression from hyperplasia through to carcinoma. Recent work from our laboratory has demonstrated that cortactin overexpression directly modulates HNSCC motility and invasion by enhanced activation of Arp2/3 complex and by its tyrosine phosphorylation mediated by Src-family kinases. These studies suggest that cortactin overexpression plays a direct role in HNSCC invasion and metastasis, and likely exerts a negative influence on patient outcome. However, the precise stage in HNSCC that cortactin is overexpressed, the suitability of cortactin as a prognostic marker for HNSCC invasion, the molecules cortactin associates with and the influence of cortactin overexpression in HNSCC progression have not been investigated in detail. This proposal seeks to address these questions throught three specific aims: Aim 1 will determining the stage(s) during HNSCC progression is the cortactin locus is amplified, the protein overexpressed and when is it phosphorylated on tyrosine and serine residues. Aim 2 will identify select proteins that interact with cortactin in HNSCC cells with and without chromosome 11q13 amplification by proteomic methods. Aim 3 will develop the first transgenic mouse model of cortactin in oral cancer to evaluate how cortactin overexpression influences HNSCC development and progression. The impact of transgenic overexpression of Arp2/3 and tyrosine phosphorylation-null dominant negative cortactin point mutants will be also be evaluated. Completion of the proposed Aims will provide better understanding and insight into the function of cortactin in HNSCC, and will potentially establish cortactin as a prognostic marker for invasive/metastatic HNSCC.