Journal Article

Analysis of HER2 genomic binding in breast cancer cells identifies a global role in direct gene regulation

Carroll, Jason S., Omarjee, Soleilmane, Redmond, Aisling M., Le Romancer, Muriel, Chernukhin, Igor

2019

Overview

HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in two breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF and have identified a de novo motif at HER2 binding sites. Over 2,000 HER2 binding sites are found in both breast cancer cell lines after EGF treatment, and according to pathway analysis, these binding sites were enriched near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a small subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners in the nucleus. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Binding sites / Biochemistry, Molecular Biology / Bioinformatics / Biology / Biology and Life Sciences / Biotechnology / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cancer / Cancer cells / Cancer genetics / Cell Line, Tumor / Cellular signal transduction / Chromatin / Deoxyribonucleic acid / DNA / Enhancer Elements, Genetic / Epidermal growth factor / Epidermal growth factor receptors / Epidermal growth factors / ErbB-2 protein / Female / Gene expression / Gene Expression Regulation, Neoplastic / Gene regulation / Genes / Genetic aspects / Genetic regulation / Genomes / Genomics / Growth factors / Histones - metabolism / Humans / Kinases / Lapatinib / Life Sciences / Ligands / Mass spectrometry / Mass spectroscopy / Medical prognosis / Medical research / Medicine and Health Sciences / Metastasis / Molecular Networks / Monoclonal antibodies / Nucleotide Motifs / Phenols (Class of compounds) / Protein Binding / Protein kinases / Protein-tyrosine kinase receptors / Proteins / Receptor, ErbB-2 - metabolism / Regulatory sequences / Research and analysis methods / Scientific equipment industry / Signal transduction / Spectroscopy / Stat3 protein / Targeted cancer therapy / Transcription factors / Transcriptional Activation / Trastuzumab / Tumor cell lines / Tumors / Tyrosine