Genomic instability and proliferation/survival pathways in RB1-deficient malignancies

The SNP analysis showed that retinoblastomas displayed relatively fewer genomic copy number changes as compared to other RB1-deficient cancer cell lines. Both TRβ1 and TRβ2 knockdown led to accumulation of E2F1 and PTTG1 and increased GIN as demonstrated by an increase in polyploidy. Downregulation of PTTG1 led to a relative decrease in GIN while upregulation of PTTG1 led to a relative increase in GIN. Knockdown of E2F1 led to a downstream decrease in PTTG1 expression. Rb-knockdown also upregulated E2F1 and PTTG1 leading to increased GIN. We showed that Rb is necessary for PTTG1 inhibition and genomic stability. A relatively stable genome in retinoblastoma tumor cells is maintained by TRβ1 and TRβ2-mediated PTTG1 inhibition, counteracting Rb-deficiency-related GIN. TRβ1, TRβ2 and Rb-KD all led to the downstream PTTG1 accumulation, apparently through an activation of E2F1 resulting in extensive genomic instability as seen in other Rb-deficient tumors.