Toxicity and lifespan extension

The RB pathway is one of the best-studied and most frequently altered pathways leading to loss of proliferative control in cancer. it can be disrupted by a variety of means including, but not limited to, epigenetic silencing, allelic loss or mutation of RB1. in some cancers including breast cancer, amplification of the CCND1 gene or overexpression of cyclin D1 is commonly observed.1 in others, the CDK4 gene is amplified or mutated within the p16iNK4A-binding domain. Finally, many cancers lack p16iNK4 expression due to deletion or promoter hypermethylation of CDKN2A. By increasing cyclin D1-CDK4 kinase activity, these genetic events all restrict the ability of underphosphorylated RB to inhibit cell cycle progression. Genetic alterations at the RB1 locus, or lack of RB expression, occur in up to a third of breast cancers.2 Breast cancer can be divided into a number of biologically distinct phenotypes, and RB loss is more common in some of these subtypes, i.e. basal breast cancers, which are typically estrogen receptor (ER)-negative, poorly-differentiated and aggressive and luminal B cancers, which are a poor-prognosis subgroup accounting for approximately a third of ER-positive breast cancers.3 interestingly, RB deletion in mouse mammary progenitor cells leads to the formation of tumors with basal or luminal B characteristics,4 suggesting that RB loss may not simply be a marker of these subtypes. Confounding issues in examining the association between RB loss and breast cancer therapeutic responsiveness and outcome include the poor correlation between RB1 LOH and low or absent RB protein expression5 as well as technical difficulties in measuring RB expression by immunohistochemistry. in Cell Cycle News & Views