Development of keratoacanthomas and squamous cell carcinomas in transgenicrabbits with targeted expression of EJras oncogene in epidermis

Activated ras genes have been frequently identified in both benign and mali gnant human tumors, including keratoacanthoma and squamous cell carcinoma. In this study, we developed two lines of transgenic rabbits in which the ex pression of EJras has been specifically targeted to the rabbit epidermal ke ratinocytes, using the upstream regulatory region of cottontail rabbit papi llomavirus. All of the F1 transgenic progenies developed multiple keratoaca nthomas at about 3 days after birth. The rabbits developed an average of 20 tumors, which usually reached the size of approximately 1 cm in diameter a nd then spontaneously regressed in about 2 months, similar to keratoacantho ma regression in humans. In addition, up to 18% of the rabbits then develop ed squamous cell carcinoma at about 5 months of age. The expression of EJra s was detectable in all of the keratoacanthomas and squamous cell carcinoma s. These results strongly support the involvement of the ras oncogene in bo th the initiation and regression of keratoacanthoma, and in the development of squamous cell carcinomas. These novel transgenic rabbits, with their co nsistent tumorigenic phenotype at an early age, high similarity to the huma n lesions, and easy accessibility for examination, manipulation, biopsy, an d treatment, should provide a unique model system for studying ras activati on-related tumor initiation, regression, and progression, and for evaluatin g antitumor therapies.