期刊
CELL REPORTS
卷 29, 期 2, 页码 249-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.08.105
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资金
- Terry Fox Research Institute Program [1048]
- Canadian Institutes of Health Research Foundation award [FDN-148373]
- Canadian Epigenetics, Environment and Health Research Consortium Team grant [TEC-128089]
- Canada Research Chair in Molecular Oncology [950-231033]
- U.S. Department of Defense Congressionally Directed Medical Research Programs Breast Cancer Research Program [W81XWH-11-1-0046]
- McGill Integrated Cancer Research Training Program
- Systems Biology Program of the Canadian Institutes of Health Research
- Reseau de Recherche en Cancer of the FRQS [FRQ-34787]
- Stand Up To Cancer Canada and the Canadian Cancer Society [SU2C-AACR-DT-1815]
Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and posttreatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me(3), a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me(3) in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27m(e)3 depletion in Trastuzumab-resistant disease.
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