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Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

Oncogene volume 28, pages 1309–1319 (2009)Cite this article

Abstract

ErbB4 isoforms mediate different cellular activities depending on their susceptibility to proteolytic cleavage. The biological significance of ErbB4 cleavage in tumorigenesis, however, remains poorly understood. Here, we describe characterization of a monoclonal antibody (mAb 1479) that selectively recognizes the ectodomain of cleavable ErbB4 JM-a isoforms both in vitro and in vivo. mAb 1479 was used to analyse ErbB4 JM-a expression and ectodomain shedding in a series of 17 matched breast cancer/histologically normal peripheral breast tissue pairs. ErbB4 ectodomain was observed in 75% of tumors expressing ErbB4 but only in 18% of normal breast tissue samples expressing ErbB4. Difference in the relative quantity of ErbB4 ectodomain between normal and tumor tissue pairs was statistically significant (P=0.015). Treatment with mAb 1479 suppressed ErbB4 function by inhibiting ErbB4 tyrosine phosphorylation and ectodomain shedding, and by stimulating ErbB4 downregulation and ubiquitination. mAb 1479 suppressed both anchorage-dependent and -independent growth of human breast cancer cell lines that naturally express cleavable ErbB4 JM-a. These findings indicate that ErbB4 ectodomain shedding is enhanced in breast cancer tissue in vivo, and that mAb 1479 represents a potential drug candidate that suppresses breast cancer cell growth by selectively binding cleavable ErbB4 isoforms.

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Acknowledgements

We thank Tero Vahlberg and Tuire Palokangas for statistical analyses, and Maria Tuominen, Minna Santanen and Mika Savisalo for excellent technical assistance. This work has been supported by Academy of Finland, Finnish Cancer Organizations, Finnish Cultural Foundation, Foundation for the Finnish Cancer Institute, Jenny and Antti Wihuri Foundation, Sigrid Jusélius Foundation, Turku University Central Hospital and Research and Science Foundation of Farmos.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Genetics, Medicity Research Laboratories, University of Turku, Turku, Finland

    M Hollmén, J A Määttä & K Elenius

  2. Turku Graduate School of Biomedical Sciences, Turku, Finland

    M Hollmén

  3. Genentech Inc., South San Francisco, CA, USA

    L Bald & M X Sliwkowski

  4. Department of Oncology, Turku University Hospital, Turku, Finland

    K Elenius

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  1. M Hollmén
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Correspondence to K Elenius.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hollmén, M., Määttä, J., Bald, L. et al. Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms. Oncogene 28, 1309–1319 (2009). https://doi.org/10.1038/onc.2008.481

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