title: Arsenic activates EGFR pathway signaling in the lung.
abstract: 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. 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. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-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, 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% confidence interval 1.1-15.6) (p = 0.04). 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.
authors.affiliation: Department of Community and Family Medicine, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire 03756, USA. Angeline.Andrew@dartmouth.edu
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Mason
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duell
mesh_terms: D000328:Adult; D000368:Aged; D066258:Amphiregulin; D000704:Analysis of Variance; D001151:Arsenic / Q000032:analysis / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D001980:Bronchi / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism; D008875:Middle Aged; D009262:Nails / Q000737:chemistry; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D018053:Arsenites; D015415:Biomarkers; C530104:CCND1 protein, human; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017670:Sodium Compounds; D019938:Cyclin D1; C017947:sodium arsenite; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D001151:Arsenic