We recently showed in transgenic mice that TGFα dramatically enhances c-myc-dependent hepatocarcinogenesis. We now have found that, despite high levels of mitosis and apoptosis in c-myc/TGFα and c-myc transgenic livers, proliferation declined before the onset of tumors at 3 and 12 months of age, respectively, concomitant with increasing TGFβ1 expression. In contrast, despite the induction of p53 and p21^WAF1, c-myc and c-myc/TGFα tumors were mitotically hyperactive, displayed pRb phosphorylation, and overexpressed TGFα, c-myc, cyclin D1, cyclin B, as well as pRb-free E2F1/DP1 and E2F2/DP1 transcription factors and their target genes cyclin A and cdc2. Although they also overexpressed TGFα1, c-myc/TGFα tumors showed downregulation of p27^KiP1 and an apoptotic index strikingly lower than in c-myc-neoplasias, consistent with reduced levels of BAX and TGFβ receptor type II. Low p15^INK4B expression further suggested decreased tumor responsiveness to TGFβ. The data suggest that: 1) co-expression of c-myc and TGFα transgenes leads to selective growth advantage for hepatic (pre)neoplastic cells by deregulation of cell cycle progression and by TGFα-mediated, reduced susceptibility to apoptosis; 2) our transgenic mice represent a powerful in vivo model for studying cell cycle control and apoptosis during hepatocarcinogenesis.