Functional inactivation of the retinoblastoma tumor suppressor, RB, occurs in a large fraction of human cancers. RB plays a critical role in cell cycle control, such that loss of RB pre-disposes to aberrant transitions through cell cycle phases. In general, this function of RB loss is believed to contribute to hyperplastic proliferation in the genesis of cancer. However, in cell culture models we have found that loss of RB leads to a modest proliferative advantage at low passage. In contrast, RB-deficient cells demonstrate a significant uncoupling of DNA replication from other cell cycle processes resulting in compromised genomic integrity. The mechanism for this effect of RB loss is complex and involves multiple RB target pathways. These same effects of RB loss are recapitulated in the mouse liver, where the deletion of RB does not fuel hyperplastic proliferation, but rather facilitates inappropriate rounds of DNA replication that drives aberrant ploidy. The genesis of hepatocellular carcinoma in human populations is largely a manifestation of environmental stresses (e.g. chronic hepatitis infection or exposure to aflatoxin B1). To model these events in mice, we utilized the DNA damaging agent diethylnitrosamine (DEN) as a tumor initiator. We found that in this context, loss of RB dramatically increased tumor susceptibility. The basis for this event is an inappropriate acute response to DNA damage that further exacerbates the breakdown of genomic integrity with RB loss. Together, these studies support a novel model for RB-mediated tumor suppression in specific organs, wherein RB inhibits tumorigenesis, not by limiting proliferation, but rather by maintaining genome integrity.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]