Genetics of skin tumor promotion.

Cancer development is a multistep process that involves both the activation of protooncogenes and the inactivation of tumor suppressor genes. Furthermore, both epidemiological and experimental data indicate that a third class of genes, tumor susceptibility genes, control the propensity to develop carcinogen-induced tumors. Recent studies suggest that tumor susceptibility is determined by the combined effect of both sensitivity and resistance genes. The mouse skin model of multistage carcinogenesis is an excellent paradigm in which to study the genetics of cancer susceptibility. This is particularly true with regard to tumor promotion, a process that occurs in other organs and species including humans. We have studied the genetics of tumor promotion susceptibility in the mouse two-stage skin tumor model using crosses between sensitive DBA/2 or C3H and resistant C57BL/6 mice. Our results suggest that TPA promotion susceptibility is a multigenic trait. We have tentatively mapped one tumor susceptibility locus, Psl1, to mouse chromosome 9 and are currently identifying and characterizing candidate tumor susceptibility genes that map to this chromosomal region. The multistage model of carcinogenesis in mouse skin has, for more than 50 years, provided a conceptual framework from which to study the carcinogenesis process. Many concepts now currently applied to other tissues and model systems were originally derived from the mouse skin model. Because tumor promotion is an important component of carcinogenesis in humans, the identification of genes that modify response to tumor-promoting stimuli would be a significant advancement in our understanding of the genetic basis of susceptibility to cancer.