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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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