Elevated expression of secondary, but not early, responding genes to phorbol ester tumor promoters in papillomas and carcinomas of mouse skin.

A single topical treatment of mouse skin with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) results in transient inductions of a variety of genes. Based on the time courses of their inductions, these genes can be classified into two main groups: "early" response genes whose mRNA expression reaches a maximum 0.5-2 h after TPA treatment and "secondary" response genes whose mRNA expression is maximal 4 h or more after treatment. The nuclear oncogenes c-fos, c-myc, and c-jun belong to the early response group, whereas the metallothionein, osteopontin, and urokinase genes belong to the secondary response group. The steady-state expressions of these early and secondary response genes are all very low in normal skin, except that of c-jun, which is relatively high. Steady-state levels of expression and inducibility of these genes by TPA were not altered in initiated skin or in apparently normal skin during tumor promotion. We examined the expressions of these genes in papillomas and carcinomas produced by two-stage (initiator-promoter) and three-stage (initiator-promoter-initiator) protocols in mouse skin. Steady-state expression of the early responding nuclear oncogenes in papillomas and carcinomas was found to remain at the same low level as in normal skin. However, all the secondary responding genes were found to be expressed constitutively at high levels in these tumors. Elevated expressions of the genes for transforming growth factor alpha and beta were also observed in papillomas and to varying extents in carcinomas. These observations suggest that the regulatory machinery for transcription by the protein kinase C-mediated pathway through nuclear oncogenes is altered during the processes of tumor promotion and progression. The genes whose expression is elevated may be associated directly or indirectly with tumor promotion and progression.