Cortactin expression predicts poor survival in laryngeal carcinoma

Abstract

Amplification of the 11q13 region is one of the most frequent aberrations in squamous cell carcinomas of the head and neck region (HNSCC). Amplification of 11q13 has been shown to correlate with the presence of lymph node metastases and decreased survival. The 11q13.3 amplicon carries numerous genes including cyclin D1 and cortactin. Recently, we reported that FADD becomes overexpressed upon amplification and that FADD protein expression predicts for lymph node positivity and disease-specific mortality. However, the gene within the 11q13.3 amplicon responsible for this correlation is yet to be identified. In this paper, we compared, using immunohistochemical analysis for cyclin D1, FADD and cortactin in a series of 106 laryngeal carcinomas which gene correlates best with lymph node metastases and increased disease-specific mortality. Univariate Cox regression analysis revealed that high expression of cyclin D1 (P ¼ 0.016), FADD (P ¼ 0.003) and cortactin (P ¼ 0.0006) predict for increased risk to disease-specific mortality. Multivariate Cox analysis revealed that only high cortactin expression correlates with disease-specific mortality independent of cyclin D1 and/or FADD. Of genes located in the 11q13 amplicon, cortactin expression is the best predictor for shorter diseasespecific survival in late stage laryngeal carcinomas. Current methods to predict the outcome of head and neck squamous cell carcinoma (HNSCC) patients mainly involve clinicopathological parameters such as tumour size, differentiation grade and presence of lymph node metastasis. Patients with laryngeal squamous cell carcinomas (LSCC) have not shown an increase in 5-year survival rates over the last 30 years (Almadori et al, 2005). Therefore, other parameters such as molecular markers that are able to more accurately predict the outcome of disease, are needed.A frequent molecular event in HNSCC is amplification of the 11q13 region (36%) (Schuuring, 1995;Freier et al, 2006). Amplification of this region in HNSCC has been associated with decreased survival (Akervall et al, 1995;Meredith et al, 1995), increased distant metastasis (Namazie et al, 2002) and lymph node metastasis (Chen et al, 2004;Hermsen et al, 2005;Xia et al, 2007). It is believed that amplification increases gene dosage and expression of genes within the amplified region (amplicon) (Albertson, 2006). Recently, we reported that the commonly amplified region is located at 11q13.3 and contains at least six genes (cyclin D1, TAOS1, FGF19, FADD, PPFIA1 and cortactin) that are overexpressed when amplified (Gibcus et al, 2007b). We concluded that the selection for tumour cells with the 11q13.3 amplicon during tumorigenesis could be based on the increased doses of one or more of these genes. We proposed FADD as a possible candidate for this selection, since FADD showed the best correlation between DNA amplification and increased expression (Gibcus et al, 2007b). Furthermore, FADD protein expression correlated with disease specific mortality (DSM) in a series of late stage laryngeal carcinom...

Cortactin and Focal Adhesion Kinase as Predictors of Cancer Risk in Patients with Laryngeal Premalignancy

“…CTTN encodes the actin-binding protein cortactin that regulates membrane dynamics, actin network assembly, cell-cell adhesion, invadopodia formation, and matrix degradation, thereby promoting cell motility and invasion (10)(11)(12). We and others have consistently shown that CTTN gene amplification and protein overexpression correlated with poor prognosis and reduced patient survival in HNSCC (13)(14)(15) and other carcinomas (16)(17)(18), thus reinforcing the central role of CTTN in the 11q13 amplicon and also in tumor progression. Nevertheless, the role of CTTN/cortactin in the early stages of tumorigenesis and its possible implication in malignant transformation and acquisition of an invasive phenotype remains to be determined.…”

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

“…Previous clinical studies of another invadopodia component, cortactin, indicate that its elevated expression and dysregulated cellular localization correlate with poor survival in laryngeal carcinoma and lung adenocarcinoma, respectively, underlining the relevance of invadopodia activity in predicting clinical outcomes (Gibcus et al 2008;Hirooka et al 2011). Consistent with these studies, our data show that a high level of Tks5 long expression and a low level of Tks5 short expression correlate with metastatic progression of lung adenocarcinoma patients and predict poor survival of patients with early stage disease, suggesting that the Tks5 long to Tks5 short ratio may serve as a prognostic marker for assessing the metastatic potential of primary tumors and for identifying early stage patients who bear higher risks for metastasis and may benefit from adjuvant therapy after tumor resection.…”

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

“…Cortactin (CTTN gene) has also been suggested as a potential metastatic driver from the 11q13.3 band, mediating an epithelial-to-mesenchymal switch through interactions with cytoskeletal components (Patel et al, 1998;van Rossum et al, 2006;Rothschild et al, 2006;Luo et al, 2006;Gibcus et al, 2008;Yamada et al, 2010). Regardless of mechanism, our results suggest that ANO1 copy number gain could act as a strong predictive marker for HPSCC tumours with a high risk of nodal metastasis.…”