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

Patients with hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer represent a historically underrecognized subgroup demonstrating poor response to combined endocrine and HER2-targeted therapies. In this study, using single-cell transcriptomic and epigenomic sequencing of estrogen receptor-positive (ER+)/HER2+ models, we identified BRD8, an acetyl-lysine reader in the EP400 histone acetyltransferase complex, as a critical mediator of ER/HER2 signaling cross-talk. BRD8 expression rapidly increased following anti-HER2 treatment, whereas its depletion disrupted ER-HER2 interaction and enhanced drug sensitivity. Single-nucleus assay for transposase-accessible chromatin using sequencing revealed that chromatin regions opening after anti-HER2 treatment were enriched for ER, FOX, and ETS transcription factor motifs, coinciding with BRD8-dependent gene activation through EP400-mediated acetylated H2AZ deposition. BRD8 regulated ER-dependent and ER-independent growth pathways, and depletion of BRD8 abolished neratinib-induced ER activation and restored drug sensitivity in resistant cells. A three-gene BRD8 signature successfully predicted anti-HER2 therapy response in two human clinical trials. Together, these findings establish BRD8 as both a predictive biomarker for anti-HER2 response and a therapeutic target to overcome resistance in HR+/HER2+ breast cancer. SIGNIFICANCE: Multiomic single-cell profiling of breast cancer identified BRD8 as a critical mediator of resistance to HER2-targeted therapies that enables ER-HER2 cross-talk and serves as a predictive biomarker for treatment response.