GSE136157 Microarray analysis of ErbB2-driven mouse mammary tumour cells treated with GSK-126

Contributors : Alison Hirukawa ; William J MullerSeries Type : Expression profiling by arrayOrganism : Mus musculusMonoclonal 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 exhibits de novo resistance. Here, by comparing matched Trastuzumab-na ïve and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, 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 Typ e-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of IFN-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote IFN-dri ven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Mus musculus Source Type: research