Nature | 是卫士，还是内应？抑癌蛋白Rb的“双面人生”

TL;DR - A Nature study shows that the Rb tumor suppressor has a dual role in HR+ breast cancer: CDK4/6 inhibition activates Rb to suppress cell-cycle genes but also drives estrogen-responsive, pro-proliferative transcription. This mechanism explains both the benefit of combining CDK4/6 inhibitors with anti-estrogen therapy and reduced efficacy in ESR1-mutant tumors.

• CUT&RUN mapping revealed that activated, hypophosphorylated Rb relocates to promoters and enhancers, joining ER-enriched 3D transcriptional hubs that activate genes such as CCND1.
• CRISPR disruption of Rb-bound enhancers and RB1 knockout eliminated drug-induced estrogen-response gene activation, supporting a direct regulatory role.
• Rb interacts with ER and KDM5A, counteracting KDM5A-mediated repression and expanding H3K4me3 across ER target genes.
• Fulvestrant blocked this proliferative feedback in endocrine-sensitive models; in ESR1-mutant models, degrading mutant ER restored stronger cell-cycle suppression.