RB depletion is required for the continuous growth of tumors initiated by loss of RB

The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here we describe a new mouse model to investigate the consequences of RB loss and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to RB knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo. We generated mice in which RB levels can be manipulated, using an inducible shRNA system with a miR-E-based, doxycycline-regulated (Tet-ON), GFP-linked shRNA at the Col1a1 locus. RNA seq was performed on pituitary samples after several weeks of RB KD and after different timepoints after reintroduction (long-term reintroduction & short-term reintroduction).