Rb-driven transcription limits its tumour-suppressive effects in breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Retinoblastoma protein (Rb) is a tumor suppressor regulating cell cycle progression by inhibiting E2F transcription factors.
• In hormone receptor-positive (HR+) breast cancer, CDK4/6 inhibitors activate Rb, a critical part of endocrine therapy.
• The mechanisms by which pharmacologically activated Rb influences chromatin and transcription beyond cell cycle arrest are not fully understood.

Purpose of the Study:

• To investigate how CDK4/6 inhibition-induced Rb activation remodels chromatin and affects gene transcription in HR+ breast cancer.
• To elucidate the role of Rb in regulating oestrogen receptor (ER) target genes and its implications for endocrine therapy.

Main Methods:

• Chromatin immunoprecipitation to assess Rb binding to promoters and enhancers.
• Gene expression analysis in breast cancer cells, patient-derived xenografts, and clinical samples.
• Investigation of the interaction between Rb and KDM5A in gene regulation.

Main Results:

• CDK4/6 inhibition causes hypophosphorylated Rb to redistribute to promoters and enhancers.
• Rb represses cell cycle genes but also promotes oestrogen-responsive gene expression by integrating into ER transcriptional hubs.
• This Rb-driven pro-proliferative program enhances ER target gene expression in an Rb-dependent manner, impacting therapeutic response.

Conclusions:

• Rb acts as a dual transcriptional regulator, capable of both enforcing cell cycle arrest and activating pro-proliferative programs.
• The Rb-driven ER transcriptional program contributes to therapeutic synergy in endocrine-sensitive tumors but limits CDK4/6 inhibitor efficacy in endocrine-resistant settings (e.g., ESR1-mutant breast cancer).
• Understanding Rb's complex role is crucial for optimizing breast cancer treatment strategies.