A dominant-negative N-terminal fragment of HER2 frequently expressed in breast cancers.
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.
Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
B
B
Morancho
J L
JL
Parra-Palau
Y H
YH
Ibrahim
C
C
Bernadó Morales
V
V
Peg
J J
JJ
Bech-Serra
A
A
Pandiella
F
F
Canals
J
J
Baselga
I
I
Rubio
J
J
Arribas
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008954:Models, Biological; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human