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

ABSTRACT: The retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression. In hormone receptor-positive breast cancer, CDK4/6 inhibitors activate Rb by preventing its phosphorylation, forming a key component of current endocrine therapy regimens. How pharmacologically activated Rb remodels chromatin and influences transcriptional networks beyond cell cycle arrest remains poorly understood. Here, we validated the specificity of the Rb antibody for CUT&RUN, and measured changes in Rb chromatin binding after treatment with abemaciclib. We show that CDK4/6 inhibition induces widespread redistribution of Rb to both promoters and enhancers in cancer cells. While Rb predictably binds to cell cycle gene promoters where it represses transcription, at other sites it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336741 | GEO | 2026/06/29

REPOSITORIES: GEO