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The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene

Oncogene volume 28, pages 4041–4052 (2009)Cite this article

Abstract

Neuregulin-1 (NRG1) is both a candidate oncogene and a candidate tumour suppressor gene. It not only encodes the heregulins and other mitogenic ligands for the ERBB family, but also causes apoptosis in NRG1-expressing cells. We found that most breast cancer cell lines had reduced or undetectable expression of NRG1. This included cell lines that had translocation breaks in the gene. Similarly, expression in cancers was generally comparable to or less than that in various normal breast samples. Many non-expressing cell lines had extensive methylation of the CpG island at the principal transcription start site at exon 2 of NRG1. Expression was reactivated by demethylation. Many tumours also showed methylation, whereas normal mammary epithelial fragments had none. Lower NRG1 expression correlated with higher methylation. Small interfering RNA (siRNA)-mediated depletion of NRG1 increased net proliferation in a normal breast cell line and a breast cancer cell line that expressed NRG1. The short arm of chromosome 8 is frequently lost in epithelial cancers, and NRG1 is the most centromeric gene that is always affected. NRG1 may therefore be the major tumour suppressor gene postulated to be on 8p: it is in the correct location, is antiproliferative and is silenced in many breast cancers.

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Acknowledgements

We thank Huai-En Huang for some exploratory expression analysis. This study was funded principally by the Breast Cancer Campaign and also by Cancer Research UK, Hutchison-Whampoa Ltd. (who endowed the buildings in which the work was done) and the Ludwig Institute for Cancer Research.

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Author notes

  1. Y L Chua

    Present address: 5Current address: Department of Haematology, University of Cambridge, Diagnostics Development Unit, NHS Blood and Transfusion Centre, Long Road, Cambridge CB2 2PT, UK,

  2. J C M Pole

    Present address: 6Current address: BlueGnome Ltd, Mill Court, Cambridge CB22 5LD, UK.,

  3. R C Stein

    Present address: 7Current address: Department of Oncology, UCL Hospitals, 250 Euston Road, London NW1 2PG, UK.,

  4. M J O'Hare

    Present address: 8Current address: Department of Neurodegenerative Disease, Institute of Neurology, London WC1N 3BG, UK.,

Authors and Affiliations

  1. Department of Pathology and Hutchison/Medical Research Council (MRC) Research Centre, University of Cambridge, Cambridge, UK

    Y L Chua, J C M Pole, S Newman & P A W Edwards

  2. Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Cambridge, Li Ka-Shing Centre, UK

    Y Ito, S -F Chin, C Caldas & A Murrell

  3. Ludwig Institute for Cancer Research/University College London Breast Cancer Laboratory, University College and Middlesex Medical School, London, UK

    R C Stein & M J O'Hare

  4. Department of Histopathology, University of Nottingham Molecular Medical Sciences, Nottingham City Hospital, Nottingham, UK

    I O Ellis

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Correspondence to P A W Edwards.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Chua, Y., Ito, Y., Pole, J. et al. The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene 28, 4041–4052 (2009). https://doi.org/10.1038/onc.2009.259

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