Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, 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 α6β4 promotes cell survival. TP53 mutations and integrin α6β4 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 β4 expression with clinicopathologic features and survival in non–small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 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 β4 overexpression 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 β4 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 β4 is overexpressed in NSCLC where it is an adverse prognostic marker.

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Published in Human Pathology, v. 54, p. 174-183.

© 2016 Elsevier Inc. All rights reserved.

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The document available for download is the authors' post-peer-review final draft of the article.

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This work was supported by the National Institutes of Health grants T32 CA160003 (R. L. S.) and R01 CA109136 (K. L. O.), the National Center for Research Resources and the National Center for Advancing Translational Sciences grant UL1TR000117 (M. C.), the American Cancer Society Institutional Research grant IRG-85-001-25 (M. C.), and the Dr Joseph F. Pulliam Pilot Award (M. C. and R. L. S.).