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  • Original Paper
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Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumour cell proliferation

Oncogene volume 20, pages 2101–2111 (2001)Cite this article

Abstract

Overexpression of the HER2 (neu/c-erbB-2) oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. Expression and secretion of aberrant HER2 splice variants has been reported in various cell lines and tissues and can interfere with the oncogenic HER2 activity. Here we demonstrate, using two different approaches, that expression of a truncated 100 kDa HER2 variant which encodes the extracellular domain of HER2 (HER-ECD) inhibits growth factor-mediated tumour cell proliferation. A HER2-ECD cDNA encoding the truncated variant was overexpressed in MCF7 breast cancer cells. HER2-ECD overexpression decreased spontaneous proliferation of MCF7 cells as well as heregulin-mediated soft agar colony formation. Concomitantly, heregulin-induced phosphorylation of HER4 as well as downstream activation of p44/p42 MAP-kinases was decreased. To confirm these data, ribozymes were targeted to the 3′-untranslated region of the 2.3 kb HER2-ECD mRNA which is spontaneously expressed in MKN7 gastric cancer cells. HER2-ECD-targeted ribozymes downregulated HER2-ECD expression and enhanced EGF-mediated soft agar colony formation of MKN7 cells. In parallel, EGF-induced activation of p44/p42 MAP-kinases and activation of c-Fos expression were increased in ribozyme-transfected MKN7 cells. Finally, in RT–PCR we found a trend towards a progressive loss of 2.3 kb HER2-ECD mRNA expression in more advanced gastric tumours. These data show that the HER2-ECD variant inhibits growth factor-mediated tumour cell proliferation suggesting an important role during the progression of human cancer.

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Acknowledgements

We thank Dr A Wellstein (Lombardi Cancer Center, Washington DC) for insightful discussions and helpful suggestions. We gratefully acknowledge the support provided by the US Army Medical Research Materiel Command Breast Cancer Program (DAMD 17-96-I-6030; to F Czubayko), by the Deutsche Forschungsgemeinschaft (DFG, Germany Ju 389/1-1; to H Juhl and F Czubayko) and by the Lombardi Cancer Center Flow Cytometry / Cell sorting shared resource (supported by the US Public Health Service grant; 2P30-CA-51008).

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  1. Achim Aigner and Hartmut Juhl: A Aigner and H Juhl contributed equally to the work

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, D-35033 Marburg, Germany

    Achim Aigner, Claudius Malerczyk & Frank Czubayko

  2. Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington, 20007, DC, USA

    Hartmut Juhl

  3. Department of Surgery, University Hospital of Kiel, D-24105 Kiel, Germany

    Anja Tkybusch

  4. Division of Hematology-Oncology, University of California, San Francisco, California, USA

    Christopher C Benz

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  1. Achim Aigner
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Aigner, A., Juhl, H., Malerczyk, C. et al. Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumour cell proliferation. Oncogene 20, 2101–2111 (2001). https://doi.org/10.1038/sj.onc.1204305

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