CDK4 is a serine/threonine kinase that forms complexes with cyclin D to regulate cell cycle progression through the G1/S transition 1. The CDK4-cyclin D complex phosphorylates retinoblastoma (RB) protein, causing its dissociation from E2F transcription factors and enabling expression of S-phase genes 2. CDK4 also phosphorylates SMAD3 to repress its transcriptional activity and integrates mitogenic and antimitogenic signals. CDK4 is critical for initiating and maintaining proliferation in hormone receptor-positive breast cancer, where it becomes a therapeutic target 1. CDK4/6 inhibitors have become standard care for advanced HR+/HER2- breast cancer, arresting sensitive cells in G1 phase 3. However, resistance mechanisms frequently emerge, including MYC-induced RB1 degradation 4 and upregulation of cyclin D1/CDK4 through PI3K/mTOR pathway activation 5. CDK4-selective inhibitors show promise in improving therapeutic efficacy while reducing hematologic toxicity compared to dual CDK4/6 inhibitors 6. Understanding CDK4's role in cell cycle control and resistance mechanisms informs development of improved treatment strategies for hormone-responsive cancers.