Besides the classical cell-autonomous tumor suppressor function of RB-E2F axis, our results show non-cell-autonomous effects arising as a consequence of cell-cycle-dependent RBL2/pRb-E2F4/1 function that guides cell fate specification through temporal fluctuations of WNT/β-catenin and DLL/NOTCH developmental signaling pathways. Here, RB1 is linked to neoplasm.