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Chemoprevention of UV Light-Induced Skin Tumorigenesis by Inhibition of the Epidermal Growth Factor Receptor

¹ Department of Biomedical Sciences, School of Medicine and ² Department of Pathology, Creighton University, Omaha, Nebraska and ³ National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Requests for reprints: Laura A. Hansen, Department of Biomedical Sciences, School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178. Phone: 402-280-4085; Fax: 402-280-2690; E-mail: lhansen{at}creighton.edu.

The epidermal growth factor receptor (EGFR) is activated in skin cells following UV irradiation, the primary cause of nonmelanoma skin cancer. The EGFR inhibitor AG1478 prevented the UV-induced activation of EGFR and of downstream signaling pathways through c-Jun NH₂-terminal kinases, extracellular signal-regulated kinases, p38 kinase, and phosphatidylinositol 3-kinase in the skin. The extent to which the UV-induced activation of EGFR influences skin tumorigenesis was determined in genetically initiated v-ras^Ha transgenic Tg.AC mice, which have enhanced susceptibility to skin carcinogenesis. Topical treatment or i.p. injection of AG1478 before UV exposure blocked the UV-induced activation of EGFR in the skin and decreased skin tumorigenesis in Tg.AC mice. AG1478 treatment before each of several UV exposures decreased the number of papillomas arising and the growth of these tumors by 50% and 80%, respectively. Inhibition of EGFR suppressed proliferation, increased apoptotic cell death, and delayed the onset of epidermal hyperplasia following UV irradiation. Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure. Thus, the UV-induced activation of EGFR promotes skin tumorigenesis by suppressing cell death, augmenting cell proliferation, and accelerating epidermal hyperplasia in response to UV. These results suggest that EGFR may be an appropriate target for the chemoprevention of UV-induced skin cancer.

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