Human papillomavirus 16 E5 oncogene contributes to two stages of skin carcinogenesis

High-risk human papillomaviruses (HPVs), which cause the vast majority of cervical cancer, other anogenital cancers, and a subset of head and neck squamous cell carcinomas, encode three oncogenes: E5, E6, and E7. To determine the oncogenic properties of HPV16 E5 in vivo, we previously generated K14E5 transgenic mice, in which expression of E5 was directed to the basal compartment of stratified squamous epithelia. In these mice, E5 induced epidermal hyperplasia and spontaneous skin tumors. In the current study, we determined how E5 contributes to tumor formation in the skin using a multistage model for skin carcinogenesis that specifies the role of genes in three stages: initiation, promotion, and malignant progression. Both initiation and promotion are required steps for papilloma formation. K14E5 mice treated with the initiating agent 7,12-dimethylbenz(a)anthracene (DMBA) developed more papillomas than like-treated nontransgenic mice, whereas neither K14E5 nor nontransgenic mice treated with the promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) developed papillomas. K14E5 mice treated with both DMBA and TPA to induce large numbers of papillomas had a higher incidence and earlier onset of carcinoma progression compared with like-treated nontransgenic mice. Thus, HPV16 E5 contributes to two stages of skin carcinogenesis: promotion and progression. The progressive neoplastic disease in K14E5 mice differed from that in nontransgenic mice in that benign tumors converted from exophytic to endophytic papillomas before progressing to carcinomas. Initial genetic and immunohistopathologic analyses did not determine the underlying basis for this distinct morphology, which correlates with a highly penetrant neoplastic phenotype.