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Updated: May 21, 2026
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
A dominant-negative N-terminal fragment of HER2 frequently expressed in breast cancers
B Morancho1, J L Parra-Palau, Y H Ibrahim
1Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
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.
Insights
A novel HER2 (human epidermal growth factor receptor 2) fragment, H2NTF, can cause resistance to anti-HER2 therapies like trastuzumab in breast cancer cells. However, H2NTF also enhances antibody-dependent cell-mediated cytotoxicity in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key target in breast cancer treatment.
- Anti-HER2 therapies, such as trastuzumab, are effective but face challenges due to tumor heterogeneity and resistance.
- Understanding novel mechanisms of resistance is crucial for improving therapeutic strategies.
Purpose of the Study:
- To investigate the role of a novel N-terminal fragment of HER2, termed H2NTF, in breast cancer.
- To characterize the interaction of H2NTF with HER2 and other HER receptors.
- To determine the impact of H2NTF expression on response to anti-HER2 therapy.
Main Methods:
- Analysis of H2NTF expression in breast cancer samples.
- Biochemical characterization of H2NTF, including its interaction with HER receptors.
- In vitro and in vivo studies assessing the effect of H2NTF on trastuzumab efficacy.
Main Results:
- H2NTF is expressed in 60% of analyzed breast cancer samples.
- H2NTF lacks the tyrosine kinase domain but interacts with full-length HER2 and other HER receptors.
- H2NTF expression confers in vitro resistance to low-dose trastuzumab by acting as a dominant-negative regulator.
- In vivo, H2NTF-expressing cells show similar sensitivity to trastuzumab, with complexes triggering antibody-dependent cell-mediated cytotoxicity.
Conclusions:
- H2NTF is a novel HER2-related protein implicated in breast cancer.
- H2NTF modulates HER2 signaling and influences response to trastuzumab.
- The dual effect of H2NTF, causing in vitro resistance but enhancing in vivo efficacy via ADCC, highlights its complex role in anti-HER2 therapy.
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