Reciprocal inactivation of the retinoblastoma tumor suppressor pathway in cancer. There are three primary mechanisms through which the retinoblastoma tumor suppressor (RB) pathway is inactivated in cancers that exhibit signature features. (Top) RB loss by genetic or epigenetic mechanisms results in the loss of the RB protein that is typically accompanied by exceedingly high levels of p16ink4a and relatively low levels of cyclin D1. (Middle) Cyclin D1 or CDK4/6 overexpression amplification is associated with intact RB and the relatively low levels of p16ink4a observed in normal tissue. (Bottom) Loss of p16ink4a is associated with intact RB and conventional levels of cyclin D1, as would be observed in a proliferative tissue. CDK, cyclin-dependent kinase; P, phosphorylated.