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Intratumoral Epiregulin Is a Marker of Advanced Disease in Non–Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells

Authors' Affiliations: Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Pathology, and ³ Biostatistics and Applied Mathematics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁴ UPRESEA3493, Centre Hospitalier Universitaire Saint-Antoine, Université Paris VI, Paris, France

Correspondence: Requests for reprints: Jonathan M. Kurie, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-6363; Fax: 713-796-8655; E-mail: jkurie{at}mdanderson.org.

Abstract

Non–small cell lung cancer (NSCLC) cells with activating epidermal growth factor receptor (EGFR) somatic mutations have unique biological properties, including high expression of the ErbB ligand epiregulin; however, the biological role of epiregulin in these cells has not been elucidated. To examine its role, we used an immunohistochemical approach to detect epiregulin expression in NSCLC biopsy samples and pharmacologic and genetic approachesto inhibit epiregulin in cultured NSCLC cells. In NSCLC biopsy samples, epiregulin was detected in 237 of 366 (64.7%) tumors, which correlated with nodal metastasis and a shorter duration of survival. In EGFR-mutant NSCLC cell lines, treatment with a small-molecule EGFR tyrosine kinase inhibitor diminished mRNA levels of the gene encoding epiregulin (EREG). The ability of EGFR-mutant NSCLC cells to invade through Matrigel in vitro was inhibited by treatment with an anti-epiregulin neutralizing antibody or by transfection with an EREG short hairpin RNA. Collectively, these findings show that epiregulin expressioncorrelated with advanced disease, was EGFR dependent, and conferred invasive properties on NSCLC cells. Additional studies are warranted in NSCLC patients to evaluate whether epiregulin expression predicts the metastatic potential of primary tumors and whether anti-epiregulin treatment strategies are efficacious in the prevention of metastasis.

Key Words: non–small cell lung cancer • epidermal growth factor receptor • epiregulin • metastasis