This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Woodworth, C. D. Articles by Nees, M. Search for Related Content PubMed PubMed Citation Articles by Woodworth, C. D. Articles by Nees, M.

Targeted Disruption of the Epidermal Growth Factor Receptor Inhibits Development of Papillomas and Carcinomas from Human Papillomavirus-immortalized Keratinocytes

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892-4255

The epidermal growth factor receptor (EGF-R) is frequently overexpressed in human papillomavirus (HPV)-associated dysplasias and carcinomas, implying that it is important for the progression of keratinocytes to malignancy. We used mice with a targeted disruption of the EGF-R gene to directly examine its role in cell immortalization and tumor development. Epidermal keratinocytes were cultured from EGF-R knockout, heterozygous, and wild-type mice, infected with retroviruses encoding HPV-16 E6 and E7 oncogenes, and grafted to nude mice. E6/E7 induced immortalization of EGF-R wild-type cells 5-fold more efficiently than null cells. Immortal EGF-R null cells grew more slowly, achieved a lower saturation density, and were more sensitive to apoptosis than the immortalized wild-type or heterozygous cells. Analyses using cDNA expression arrays showed that EGF-R null cells expressed increased levels of RNAs encoding p21^waf and insulin-like growth factor-binding protein-2. EGF-R-positive immortal keratinocytes formed papillomas in 17% (15 of 90) of skin grafts, and seven grafts progressed to squamous carcinoma after 6–12 months. EGF-R null keratinocytes did not form papillomas, but 1 of 96 grafts progressed to a squamous carcinoma after 1 year. However, treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate induced tumors in 18 and 35% of grafts containing EGF-R null or EGF-R-positive cells, respectively. Transduction with an activated v-Ha-ras gene, which signals downstream of the EGF-R, induced rapidly growing carcinomas in all grafts regardless of EGF-R genotype. These results directly show that the EGF-R is important, but not essential, for immortalization by HPV and for progression of immortal cells to papillomas and carcinomas.

This article has been cited by other articles:

				D. Brennan, Y. Hu, S. Joubeh, Y. W. Choi, D. Whitaker-Menezes, T. O'Brien, J. Uitto, U. Rodeck, and M. G. Mahoney Suprabasal Dsg2 expression in transgenic mouse skin confers a hyperproliferative and apoptosis-resistant phenotype to keratinocytes J. Cell Sci., March 1, 2007; 120(5): 758 - 771. [Abstract] [Full Text] [PDF]

				S. J.S. Simonson, M. J. Difilippantonio, and P. F. Lambert Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential Cancer Res., September 15, 2005; 65(18): 8266 - 8273. [Abstract] [Full Text] [PDF]

				S. M. Genther Williams, G. L. Disbrow, R. Schlegel, D. Lee, D. W. Threadgill, and P. F. Lambert Requirement of Epidermal Growth Factor Receptor for Hyperplasia Induced by E5, a High-Risk Human Papillomavirus Oncogene Cancer Res., August 1, 2005; 65(15): 6534 - 6542. [Abstract] [Full Text] [PDF]

				C. D. Woodworth, E. Michael, D. Marker, S. Allen, L. Smith, and M. Nees Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment Mol. Cancer Ther., April 1, 2005; 4(4): 650 - 658. [Abstract] [Full Text] [PDF]

				M C Velarde, S I Parisek, R R Eason, F A Simmen, and R C M Simmen The secretory leukocyte protease inhibitor gene is a target of epidermal growth factor receptor action in endometrial epithelial cells J. Endocrinol., January 1, 2005; 184(1): 141 - 151. [Abstract] [Full Text] [PDF]

				B. Bostrom, J. Sidman, S. Marker, T. Lander, and D. Drehner Gefitinib Therapy for Life-Threatening Laryngeal Papillomatosis Arch Otolaryngol Head Neck Surg, January 1, 2005; 131(1): 64 - 67. [Full Text] [PDF]