Abstract GS3-06: Rb Functions as a Transcriptional Activator of ER Targets Following CDK4/6 Inhibition in Luminal Breast Cancer

Key Points

• This research aims to explore the function of Rb as a transcriptional activator in estrogen receptor-positive breast cancer following CDK4/6 inhibition.
• Mapped genome-wide Rb binding using CUT&RUN in ER+ cancer cell lines and patient-derived xenografts.
• Conducted H3K27ac HiChIP analysis to study enhancer interactions post-CDK4/6 inhibition.
• Performed transcriptomic analysis from the POP trial to assess gene expression responses to palbociclib.
• Used CRISPR-Cas9 for functional validation of Rb-bound enhancers affecting gene expression.
• CDK4/6 inhibition caused hypo-phosphorylation of Rb, increasing its chromatin binding.
• Rb was found to activate thousands of non-promoter sites linked to estrogen-responsive genes.
• Estrogen response gene sets showed significant upregulation in both cell lines and PDX tumors after treatment.
• Rb's localization influenced gene induction in wild-type ESR1 cells, but persisted despite estrogen deprivation in ESR1-mutant cells.