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Background and Aims  Up‐regulation of the E2F‐dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F‐dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity  in vivo  have been lacking.    Approach and Results  Here, we generated transgenic mice with doxycycline‐controlled transcriptional activation of  E2f7  and  E2f8  and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of  E2f7  and, to lesser extent,  E2f8  transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine‐induced liver tumors.    Conclusion  Collectively, our findings demonstrate that atypical E2Fs can override cell‐cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.

E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice