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Targeted Disruption of the Epidermal Growth Factor Receptor Impairs Growth of Squamous Papillomas Expressing the v-ras^Ha Oncogene but Does Not Block in Vitro Keratinocyte Responses to Oncogenic ras

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892 [A. A. D., L. H., C. C., N. A., M. F. D., S. H. Y.]; Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106 [D. W. T., T. M.]; and Departments of Cell Biology and Medicine, Vanderbilt University, Nashville, Tennessee 37232 [R. J. C.]

We have assessed the role of epidermal growth factor receptor (EGFR) signaling in biological responses to the v-ras^Ha oncogene using primary keratinocytes from Egfr -/- mice and wild-type littermates. On the basis of several criteria, Egfr -/- keratinocytes were unresponsive to either acute or chronic exposure to several EGFR ligands but were stimulated to proliferate in response to several other mitogens. Although conditioned medium from primary keratinocytes transduced with v-ras^Ha retrovirus (v-ras^Ha keratinocytes) was a potent mitogen for wild-type but not Egfr -/- keratinocytes, v-ras^Ha transduction of primary keratinocytes of either genotype resulted in a strong mitogenic response, arguing against an obligatory role for EGFR activation in v-ras^Ha-mediated stimulation of keratinocyte proliferation. Infection with high-titer v-ras^Ha retrovirus altered the keratin expression pattern in keratinocytes of both genotypes, suppressing differentiation-specific keratins K1 and K10 while activating aberrant expression of K8 and K18. In wild-type but not Egfr -/- cultures, K1 and K10 were also suppressed following infection at lower retroviral titers, presumably as a result of paracrine EGFR activation on uninfected cells present in these cultures. Squamous papillomas produced by grafting Egfr -/- v-ras^Ha keratinocytes onto nude mice were only 21% of the size of wild-type v-ras^Ha tumors, and a striking redistribution of S-phase cells was detected by immunostaining for bromodeoxyuridine. In Egfr -/- v-ras^Ha papillomas, the fraction of total labeled nuclei detected in suprabasal layers was increased from 19 to 39%. In contrast, the basal layer labeling index of Egfr -/- papillomas was reduced to 34%, compared to 43% in wild-type tumors. Our results indicate that, although autocrine EGFR signaling is not required for keratinocyte responses to oncogenic ras in culture or benign tumor formation in nude mouse grafts, disruption of this pathway impairs growth of v-ras^Ha papillomas by a mechanism that may involve alterations in keratinocyte cell cycle progression and/or migration in vivo.

¹ Present address: Department of Dermatology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109.

² Present address: Department of Pathology, Northwestern University Medical School, Chicago, IL 60611.

³ Present address: Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.

⁴ To whom requests for reprints should be addressed, at LCCTP/NCI/NIH, Building 37/Room 3B25, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255. E-mail: yuspas@dc37a.nci.nih.gov.

Received 2/25/97. Accepted 5/29/97.

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