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

B. Morancho, J. L. Parra-Palau, Y. H. Ibrahim, C. Bernadó Morales, V. Peg, J. J. Bech-Serra, A. Pandiella, F. Canals, J. Baselga, I. Rubio, J. Arribas

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5 Citations (Scopus)

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. © 2013 Macmillan Publishers Limited. All rights reserved.
Original languageEnglish
Pages (from-to)1452-1459
JournalOncogene
Volume32
Issue number11
DOIs
Publication statusPublished - 14 Mar 2013

Keywords

  • breast cancer
  • ErbB2
  • HER2

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