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A dominant-negative N-terminal fragment of HER2 frequently expressed in breast cancers

Oncogene volume 32, pages 1452–1459 (2013)Cite this article

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Abstract

The transmembrane tyrosine kinase HER2 (ErbB2, neu) is a prototypical biomarker for breast cancers and a therapeutic target. Although anti-HER2 therapies are remarkably effective, HER2-positive tumors are heterogeneous and some subtypes do not respond or develop resistance to these therapies. Here we show that H2NTF, a novel N-terminal fragment of HER2, is expressed at variable levels in 60% of the breast cancer samples analyzed. Characterization of H2NTF shows that it is devoid of the tyrosine kinase domain but it readily interacts with full-length HER2 and other HER receptors. As a consequence, H2NTF acts as a dominant-negative, attenuating the signaling triggered by full-length HER receptors. Expression of H2NTF results in resistance to the treatment with low concentrations of trastuzumab in vitro. However, cells expressing H2NTF and non-expressing cells have similar sensitivity to trastuzumab in vivo, indicating that H2NTF/trastuzumab complexes trigger antibody-dependent cell-mediated cytotoxicity.

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Acknowledgements

This work was supported by Instituto de Salud Carlos III (Intrasalud PI081154, PI11/02496 and the network of cooperative cancer research (RTICC-RD06/0020/0022 and RTICC-RD06/0020/0041)), GlaxoSmithKline and the Breast Cancer Research Foundation (BCRF).

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Authors and Affiliations

  1. Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    B Morancho, J L Parra-Palau, Y H Ibrahim, C Bernadó Morales, J J Bech-Serra, F Canals, J Baselga & J Arribas

  2. Pathology Department, Vall d'Hebron University Hospital and Department of Morphological Sciences, Universitat Autonoma de Barcelona, Bellaterra, Spain

    V Peg

  3. Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

    A Pandiella

  4. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    J Baselga

  5. Breast Surgical Oncology, Breast Cancer Center, Vall d'Hebron University Hospital, Barcelona, Spain

    I Rubio

  6. Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain

    J Arribas

  7. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    J Arribas

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  1. B Morancho
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  2. J L Parra-Palau
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  8. F Canals
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  9. J Baselga
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Correspondence to J Arribas.

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Morancho, B., Parra-Palau, J., Ibrahim, Y. et al. A dominant-negative N-terminal fragment of HER2 frequently expressed in breast cancers. Oncogene 32, 1452–1459 (2013). https://doi.org/10.1038/onc.2012.152

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  • DOI: https://doi.org/10.1038/onc.2012.152

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