CDK4 and breast cancer: The phosphorylation of the retinoblastoma protein allowed by cyclin D/CDK4/6 causes the detachment of retinoblastoma protein from the E2F transcription factor, leading to the transcription of multiple target genes including MDM2. The activity of palbociclib, a CDK4/CDK6-inhibitor currently approved in breast cancer, in CDK4-positive WDLS/DDLS was shown in a phase 2 study reporting a 12-week PFS rate of 66% [80].