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c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer

Oncogene volume 33, pages 3992–4002 (2014)Cite this article

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Abstract

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial–mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2+ breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2+ breast cancer.

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Acknowledgements

We thank Professor JM Bishop and The GW Hooper Foundation (UCSF); Nikki Ailing and Alice Boulghourjian for technical assistance with Flow cytometry and Immunohistochemistry, respectively; and Aurelie Cazet for proof reading the manuscript. WST is a recipient of an International Postgraduate Research Scholarship (IPRS) and the Beth Yarrow Memorial Award in Medical Science. We would like to acknowledge funding from Victoria Taylor, Sydney Breast Cancer Foundation, CCNSW and Colin Biggers & Paisley, Sydney. This research was supported by an Early Career Fellowship from the National Breast Cancer Foundation Australia. AS is a Career Development Fellow of the National Health and Medical Research Council of Australia. SOT is funded by the Cancer Institute NSW Clinical Research Fellowship 10-CRF 1-07.

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Authors and Affiliations

  1. Cancer Research Division, The Kinghorn Cancer Centre and Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    R Nair, D L Roden, W S Teo, A McFarland, S Junankar, S Ye, A Nguyen, J Yang, I Nikolic, M Hui, L A Baker, M J Cowley, M J Naylor, C J Ormandy, S A O'Toole & A Swarbrick

  2. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

    W S Teo, S Junankar, S Ye, A Morey, M J Naylor, C J Ormandy, W Kaplan, S A O'Toole & A Swarbrick

  3. Department of Anatomical Pathology, Sydpath, St Vincent’s Hospital, Darlinghurst, NSW, Australia

    A Morey

  4. School of Medical Sciences, University of New South Wales, Camperdown, NSW, Australia

    J Shah

  5. Department of Pathology and Laboratory Medicine, Chapel Hill, NC, USA

    A D Pfefferle & C M Perou

  6. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    A D Pfefferle, J Usary & C M Perou

  7. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    J Usary & C M Perou

  8. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    C Selinger & S A O'Toole

  9. School of Biotechnology and Biomolecular Sciences, University of New South Wales, NSW, Australia

    L A Baker

  10. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia

    N Armstrong

  11. Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    M J Cowley & W Kaplan

  12. Discipline of Physiology and Bosch Institute, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia

    M J Naylor

  13. The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Pathology Queensland, The Royal Brisbane and Women’s Hospital, Herston, Brisbane, QLD, Australia

    S R Lakhani

  14. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    J I Herschkowitz

  15. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

    S A O'Toole

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  1. R Nair
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Correspondence to A Swarbrick.

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Nair, R., Roden, D., Teo, W. et al. c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer. Oncogene 33, 3992–4002 (2014). https://doi.org/10.1038/onc.2013.368

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