Based on previous results from different laboratories, including our own, we postulate that inactivation of suppressor genes may complement the activation of the Ha-ras gene for the acquisition of a fully malignant phenotype (squamous cell carcinoma) in chemically induced skin carcinogenesis. The long term goals of this project are to show the role of tumor suppression function in this system, to identify the putative suppressor genes, and to investigate tumor suppressor mechanisms. The induction of squamous cell carcinomas (SCC) in the mouse skin by 2-stage protocols is a reliable, reproducible model in which many molecular and cellular aspects of carcinogenesis have been described and intermediate premalignant stages have been characterized, histologically, cytogenetically and biochemically. Therefore, this model appears to be ideal to investigate the tumor suppression phenomenon, not only to gain understanding of the pathobiology of human SCC, but also to elucidate general mechanisms of chemical carcinogenesis. We propose, in this project, to study the suppression phenomenon in the mouse skin system following the same approach that has been successfully used to show tumor suppression in other systems: cell fusion techniques and detection of allelic losses. Cell fusion experiments between normal and tumoral cells will show the existence of tumor suppression in this model and will also signal the chromosomal location of putative suppressor genes. The loss of heterozygosity (LOH) of polymorphic genes, a sensitive indicator of chromosomal deletion and/or allelic loss, will be used to detect putative areas of the genome with suppressor function.
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