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The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment

Oncogene volume 35, pages 6053–6064 (2016)Cite this article

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Abstract

Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20–30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal.

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Acknowledgements

We thank Dr Jonathan Rayment, Dr Dongmei Zuo, and Ms Virginie Sanguin-Gendreau for their important involvement in this project. This study was supported by grants awarded to WJM from the Terry Fox Foundation (#020002), the Canadian Institutes of Health Research (MOP 93525 and MOP 89751) and the National Institutes of Health PO1 (2PO1CA099031-06A1). WJM is supported by CRC Chair in Molecular Oncology. JT was supported by the Department of Defense Breast Cancer Predoctoral Traineeship award #W81XWH 10-1-0114. ZCH was supported by Susan G Komen Breast Cancer Foundation (CCR14299200) and NIH-NCI (T32-CA009111). ERA is supported by NIH grant R01CA160514. RDC is supported by a US-NCI grant U01 CA141582. MMTV/ErbB2 transgenic mice were a generous donation from Genentech.

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Authors and Affiliations

  1. Goodman Cancer Center, Montreal, Quebec, Canada

    J Turpin, C Ling, A M Simond, J Ozcelik, M Hallett & W J Muller

  2. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    J Turpin & W J Muller

  3. Department of Surgery, Duke University Medical Center, Durham, USA

    E J Crosby & Z C Hartman

  4. Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    L A Chodosh

  5. Department of Physiology, Michigan State University, East Lansing, MI, USA

    J P Rennhack & E R Andrechek

  6. Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA

    G B Mills

  7. Department of Pathology, Center for Comparative Medicine, University of California Davis, Davis, CA, USA

    R D Cardiff

  8. Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA

    J W Gray

  9. McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA

    O L Griffith

  10. Department of Medicine, McGill University, Montreal, Quebec, Canada

    W J Muller

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Turpin, J., Ling, C., Crosby, E. et al. The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment. Oncogene 35, 6053–6064 (2016). https://doi.org/10.1038/onc.2016.129

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