ToxSci Advance Access published online on January 23, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp015
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Arsenic activates EGFR pathway signaling in the lung
1 Department of Community and Family Medicine, Dartmouth Medical School, Dartmouth College, Hanover, NH, USA 2 Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA 3 Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA 4 Genetics and Epidemiology Cluster, World Health Organization – International Agency for Research on Cancer, Lyon, France
Corresponding Author: Dr. Angeline S. Andrew, Dartmouth Medical School, 7927 Rubin 860, One Medical Center Drive, Lebanon, NH 03756, Telephone: (603) 653-9019 Fax: (603) 653-9093, E-mail: Angeline.Andrew{at}dartmouth.edu
Received December 3, 2008; revision received January 16, 2009; accepted January 17, 2009
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Abstract |
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Background: Arsenic is an established lung carcinogen, however the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell-cycle progression, tumor invasion, and angiogenesis. Methods: We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Results: Our in vitro data suggest that arsenic increases levels of the EGFR ligand, HB-EGF and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor (EGFR-TKI), Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95%CI 1.1-15.6) (p = 0.04). Conclusions: These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.
Key Words: epidermal growth factor; lung cancer; arsenic; cyclin D1; human.