CDK4/6-Activated Rb Rewires Estrogen Signaling in Breast Cancer

In HR+ breast cancer, CDK4/6 inhibitors activate hypophosphorylated Rb, causing it to redistribute to chromatin where it represses E2F targets but unexpectedly boosts estrogen receptor–driven gene expression by forming ER-rich transcriptional hubs. This Rb-driven enhancer/promoter activity, aided by KDM5A, can promote proliferation and is mitigated by anti-estrogen therapy in endocrine-sensitive tumors, explaining their synergy. In ESR1-mutant endocrine-resistant cancers, the pro-growth ER program persists, limiting CDK4/6 inhibitor efficacy. The study maps Rb binding with CUT&RUN and HiChIP across cell lines, PDXs, and clinical samples, revealing a dual role for Rb: a tumor suppressor that also activates pro-proliferative transcriptional programs.