Integrated Multiomic Profiling Identifies BRD8/EP400 as a Pivotal Chromatin Module Mediating Anti-HER2 Response in...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer patients show poor response to current therapies.
• Understanding the molecular mechanisms driving resistance is crucial for improving treatment outcomes.

Purpose of the Study:

• To identify key mediators of ER/HER2 signaling crosstalk in HR+/HER2+ breast cancer.
• To investigate BRD8 as a potential therapeutic target and predictive biomarker for anti-HER2 therapy response.

Main Methods:

• Single-cell transcriptomic and epigenomic sequencing (including single-nucleus ATAC-sequencing) of ER+/HER2+ models.
• Functional studies involving BRD8 depletion and assessment of drug sensitivity.
• Analysis of a 3-gene BRD8 signature in human clinical trial data.

Main Results:

• BRD8 expression increases with anti-HER2 treatment and mediates ER/HER2 signaling crosstalk.
• BRD8 depletion disrupts ER-HER2 interaction, enhances drug sensitivity, and restores sensitivity in resistant cells.
• A BRD8-based gene signature predicts response to anti-HER2 therapy in clinical trials.

Conclusions:

• BRD8 is a critical mediator of resistance in HR+/HER2+ breast cancer.
• BRD8 serves as both a predictive biomarker and a therapeutic target to overcome resistance to anti-HER2 therapies.