GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336731/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336731GEOGSEfalseTranscriptomic profiling of MCF7 ESR1-PARENT and ESR1-Y537S cells cultured under estrogen-depleted or estradiol-supplemented conditions following abemaciclib treatment and CCND1 knockdownThe retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression. In hormone receptor-positive (HR+) 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 transcription beyond cell cycle arrest remains poorly understood. Here we show that CDK4/6 inhibition induces redistribution of hypo-phosphorylated Rb to promoters and enhancers. While Rb predictably binds to cell cycle gene promoters to repress transcription, at other sites it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. CDK4/6 inhibition enhances ER target gene expression in breast cancer cells, patient-derived xenografts, and clinical HR+ breast cancer samples in an Rb-dependent manner. This reprogramming is mediated in part by KDM5A, whose interaction with Rb contributes to gene regulation at these loci. Critically, components of this Rb-driven ER transcriptional program are pro-proliferative. In endocrine-sensitive tumours, this can be neutralised with anti-oestrogen therapy, explaining therapeutic synergy. In endocrine-resistant settings such as ESR1-mutant breast cancer, the program persists, limiting therapeutic efficacy. These findings reframe Rb as a dual-function transcriptional regulator that, while enforcing cell cycle arrest, can also activate programs that counteract its tumour suppressor function.2026/06/29GSE336731GSM9841480GSM9841503GSM9841469GSM9841502GSM9841501GSM9841468GSM9841489GSM9841500GSM9841488GSM9841487GSM9841486GSM9841485GSM9841484GSM9841483GSM9841482GSM9841481GSM9841491GSM9841490GSM9841479GSM9841478GSM9841477GSM9841499GSM9841498GSM9841476GSM9841497GSM9841475GSM9841496GSM9841474GSM9841495GSM9841473GSM9841472GSM9841494GSM9841493GSM9841471GSM9841492GSM984147018573336731Homo sapiens