Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer

Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin alpha 6 beta 4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin alpha 6 beta 4 promotes cell survival. TP53 mutations and integrin alpha 6 beta 4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin beta 4 expression with clinicopathologic features and survival in non small cell lung cancer (NSCLC). We constructed a lung cancer tissue micro array and stained sections for integrin beta 4 subunit expression using immunohistochemistry. We found that integrin beta 4 expression is elevated in SCC compared with adenocarcinoma (P < .0001), which was confirmed in external gene expression data sets (P < .0001). We also determined that integrin beta 4 over expression associates with the presence of venous invasion (P = .0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P = .0422). Elevated integrin beta 4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P < .0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin beta 4 is overexpressed in NSCLC where it is an adverse prognostic marker. (C) 2016 Elsevier Inc. All rights reserved.