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.), Vol.86(13)
07/01/2026
DOI: 10.1158/0008-5472.CAN-25-4701
PMCID: PMC13110125
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.), Vol.86(13)
- DOI
- 10.1158/0008-5472.CAN-25-4701
- PMID
- 41886605
- PMCID
- PMC13110125
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Grant note
- National Cancer Institute (NCI): P30CA014520 Network of the National Library of Medicine (NNLM): NLM5T15LM007359 National Institutes of Health (NIH): P01CA022443 Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison
We gratefully acknowledge Drs. Ruth M O'Regan (University of Rochester Medical Center) for an initial discussion of the project and Xinpei Ci (Princess Margaret Cancer Centre, Toronto, Canada) for technical advice. We thank Derek Pavelec (University of Wisconsin-Madison) for initial data processing of scRNA-seq. We thank Dr. Alana Welm (University of Utah) for HCI005, HCI007, and HCI032 PDX and the corresponding PDxO models. We thank the UWCCC Flow Cytometry Laboratory, Cancer Informatics Shared Resource, Experimental Animal Pathology Laboratory, Research Animal Resources and Compliance, and University of Wisconsin Biotechnology Center for technical support. This work was supported by the NIH/NCI (NIH/NCI P30CA014520 to University of Wisconsin. for salary support of W. Xu and P. Liu; NIH R01 CA281024, R01 CA268183; and R01 CA236356 to W. Xu) and by the NIH/National Library of Medicine (NIH/NLM Training Grant NLM5T15LM007359 to University of Wisconsin, supporting P.H. Khatri). NCI Breast SPORE program (P50-CA058223) and NCI R01-CA229409 supported A. Fernandez-Martinez and C.M. Perou. H.Q. Dinh was supported by start-up funds and pilot grants from University of Wisconsin-Madison SMPH and by NIH grant P01CA022443.
- Language
- English
- Electronic publication date
- 03/26/2026
- Date published
- 07/01/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985149409702771
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