Transcriptomic profiling of ZR-75-1 wild-type and RB1 knockout cells treated with abemaciclib

This reprogramming is mediated in part by KDM5A and KDM5B, whose functional interaction with Rb contributes to transcriptional regulation at these loci. In patient-derived models and clinical samples of endocrine-sensitive breast cancer, CDK4/6 inhibition enhances ER target gene expression, sensitising tumours to anti-oestrogen therapy. However, in endocrine-resistant contexts – such as ESR1-mutant breast cancer – this Rb-driven oestrogenic programme serves to limit therapeutic efficacy.

These findings reframe Rb as a dual-function transcriptional regulator – one that enforces cell cycle arrest while driving transcriptional programs with important therapeutic implications. This expanded model of Rb function provides a new mechanistic basis for the synergy between CDK4/6 inhibitors and endocrine therapy, and offers insight into resistance mechanisms in hormone receptor-positive breast cancer.