Highlights
The retinoblastoma protein (RB) signal transduction pathway suppresses tumor development and is impaired in most cancers.
RB pathway disruption in tumors promotes a broad range of malignant properties, such as cancer-associated blood vessel formation, metastasis, inflammation, immune evasion, cell survival, and metabolic reprogramming, as well as genomic instability.
Impaired RB pathway signaling in cancers promotes various types of genomic instability due to disrupted cell biological processes, including cell cycle progression, DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization.
While RB pathway alterations promote cancer development and treatment resistance, they also offer therapeutic opportunities, including some based on new concepts, such as synthetic lethality and oncolytic viruses.
Abstract
Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As ‘the guardian of the genome’, the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinoblastoma protein (RB) is ‘the sentry of cell cycle entry’, as it dictates whether a cell enters the cell cycle to divide. However, the RB pathway also controls myriad non-canonical cellular processes, including metabolism, stemness, angiogenesis, apoptosis, and immune surveillance. We discuss how frequent RB pathway inactivation and underlying mechanisms in cancers affect these processes. We focus on RB’s – rather than p53’s – ‘guardian of the genome’ functions in DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization. Finally, we review therapeutic strategies, challenges, and opportunities for targeting RB pathway alterations in cancer.