In addition, RB loss has been associated with higher tumor grade and stage in bladder cancer and shorter event-free survival (EFS) in osteosarcoma ( 9, 10).

Specifically, RB loss has been associated with shorter overall survival (OS) in multiple myeloma, bladder cancer, and early-stage non–small cell lung cancer (NSCLC refs.

Despite current understanding of RB function in preventing cellular transformation, significant gaps in understanding exist in discerning the role of RB in tumor progression.Įlucidating the role of RB loss in disease progression is critical, as RB LOF has been attributed to poor outcome in a number of tumor types. These alterations have been identified across cancers and proven to play a significant role in driving tumor phenotypes. Common alterations driving RB LOF in human malignancy include RB1 gene mutation, promoter methylation, and deep deletion, in addition to upstream pathway modulation such as upregulation of cyclins and CDKs or loss of CDKI function ( 3, 4). Loss of function (LOF) of RB alters gene networks, including but not limited to those associated with E2Fs, which have been shown to drive tumorigenesis and disease progression. In response to mitogenic stimuli, CDK/cyclin complexes hyperphosphorylate RB, promoting a conformational change and allowing for derepression of activator E2F transcription factors (E2F1, E2F2, and E2F3 refs.

Canonical RB function in cell-cycle control is tightly regulated by cyclin-dependent kinase (CDK) and cyclin phosphorylation as well as upstream CDK inhibitor (CDKI) proteins. The retinoblastoma (RB) tumor suppressor protein serves as a transcriptional corepressor that is frequently altered in cancer and has been linked to both prevention of tumor development and progression. On balance, these findings reveal novel pathways through which RB loss promotes cancer progression and highlight potentially new nodes of intervention for treating RB-deficient cancers. These E2F1-dependent events resulted in protection from reactive oxygen species in response to therapeutic intervention. Biochemical and functional assessment using both in vitro and in vivo models identified an unexpected, prominent role for E2F1 in regulation of redox metabolism after RB loss, driving an increase in the synthesis of the antioxidant glutathione, specific to advanced disease. Here, isogenic modeling of RB loss identified disease stage–specific rewiring of E2F1 function, providing the first-in-field mapping of the E2F1 cistrome and transcriptome after RB loss across disease progression. Loss of the retinoblastoma (RB) tumor suppressor protein is a critical step in reprogramming biological networks that drive cancer progression, although mechanistic insight has been largely limited to the impact of RB loss on cell-cycle regulation.

Breast Cancer at 35 by Amy Burns