Abstract
Inactivation of the RB tumor suppressor and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Loss of RB function and MYC activation are thought to control both overlapping and distinct cellular processes during cell cycle progression. However, how these two major cancer genes functionally interact during tumorigenesis is still unclear. Here, we sought to test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC), a deadly cancer type in which RB is frequently inactivated and c-MYC often activated. We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors. There was a trend for decreased survival in double mutant animals compared to mice developing c-MYC-induced tumors. Thus, loss of RB function does not provide a proliferative advantage to c-MYC-expressing HCC cells but the RB and c-MYC pathways may cooperate to control the polyploidy of mature hepatocytes.
Highlights
Cancer is a complex disease that often progresses slowly due to the gradual accumulation of genetic and epigenetic alterations over time [1,2]
In this study we investigated if loss of Retinoblastoma protein (RB) function may cooperate with activation of MYC in a mouse model of hepatocellular carcinoma (HCC)
The only identifiable difference was the degree of ploidy in pre-neoplastic tissue where MYC/Rb mutant pre-tumor tissue displayed a higher degree of ploidy than MYC mutant pretumor tissue in hepatocyte populations
Summary
Cancer is a complex disease that often progresses slowly due to the gradual accumulation of genetic and epigenetic alterations over time [1,2]. Tumor cells harbor mutations that activate oncogenes and inactivate tumor suppressors The combination of these alterations promotes deregulated cell division, one of the hallmarks of the cancer phenotype [1]. In G1, activation of Cyclin/CDK complexes by mitogenic signals results in RB phosphorylation and functional inactivation, allowing E2F family members to transcribe genes necessary for cell cycle progression [4] In addition to this well-described function of RB, emerging evidence indicates that RB normally promotes differentiation in multiple lineages [5,6,7,8,9,10,11] and protects cells from the accumulation of genomic alterations [12,13, 14,15,16,17]. Due to the critical influence of RB in the control of cell cycle progression, it is not surprising that RB or members of the RB pathway are mutated in most human cancers [18,19]
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