E2F family of transcription factors plays an important role in cell cycle regulation, oncogenesis and differentiation. E2Fs are a family of heterodimeric transcription factors composed of E2F-like and DP-like subunits. They regulate expression of specific genes controlling cellular proliferation by binding to specific sequences within the promoter regions of these target genes and affecting their transcription in a cell cycle dependent manner. Recent studies have suggested an essential role of Rb/E2F pathway in the passage of cells through the G1 phase of the cell cycle. To better understand the role of these transcription factors in epithelial tumorigenesis, we compared the expression of various proteins involved in the Rb/E2F pathway in epidermis and 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted papillomas on SENCAR mouse skin. Western blot analysis data showed 3.0- to 7.6-fold upregulation of E2F-1, E2F-2, E2F-3, E2F-4 and E2F-5 in tumors compared to normal epidermis. In tumors, the protein expression of DP-1 did not show significant change whereas that of DP-2 showed a 2.2-fold increase. Compared to normal epidermis, a significant upregulation of pRb (6.3-fold) and p107 (13-fold) was also observed in tumors. The protein expression of p130 was not detectable either in normal epidermis or in tumors. These data suggest that the overexpression of E2F proteins may be involved in the G1-S phase dysregulation that occurs during mouse skin tumorigenesis.