Journal article
Integrated Multi-omic Profiling Identifies BRD8/EP400 as a Pivotal Chromatin Module Mediating Anti-HER2 Response in HR+/HER2+ Breast Cancer
Cancer research (Chicago, Ill.)
03/26/2026
DOI: 10.1158/0008-5472.CAN-25-4701
PMID: 41886605
Abstract
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. Here, using single-cell transcriptomic and epigenomic sequencing of ER+/HER2+ models, we identified BRD8, an acetyl-lysine reader in the EP400 histone acetyltransferase complex, as a critical mediator of ER/HER2 signaling crosstalk. BRD8 expression rapidly increased following anti-HER2 treatment, while its depletion disrupted ER-HER2 interaction and enhanced drug sensitivity. Single-nucleus ATAC-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 H2AZac deposition. BRD8 regulated ER-dependent and independent growth pathways, and depletion of BRD8 abolished neratinib-induced ER activation and restored drug sensitivity in resistant cells. A 3-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.
Details
- Title: Subtitle
- Integrated Multi-omic Profiling Identifies BRD8/EP400 as a Pivotal Chromatin Module Mediating Anti-HER2 Response in HR+/HER2+ Breast Cancer
- Creators
- Ang Gao - University of Wisconsin–MadisonParth H Khatri - University of Wisconsin–MadisonGui Ma - University of Wisconsin–MadisonPeng Liu - University of Wisconsin–MadisonAranzazu Fernandez-Martinez - University of North Carolina at Chapel HillKristine Donahue - University of Wisconsin–MadisonYidan Wang - University of Wisconsin–MadisonEui-Jun Kim - Catholic Kwandong UniversityMingshan Hu - University of Wisconsin–MadisonFabao Liu - Shandong UniversityJingjing Zhou - University of Wisconsin–MadisonNgai Ting Chan - University of Wisconsin–MadisonXingjian Yang - University of Wisconsin–MadisonRene Welch Schwartz - University of Wisconsin–MadisonIrene M Ong - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin–MadisonKari B Wisinski - University of Wisconsin Carbone Cancer CenterCharles M Perou - University of North Carolina at Chapel HillHuy Q Dinh - University of Wisconsin–MadisonWei Xu - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.)
- DOI
- 10.1158/0008-5472.CAN-25-4701
- PMID
- 41886605
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Electronic publication date
- 03/26/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985149409702771
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