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Flotillins as regulators of ErbB2 levels in breast cancer

Oncogene volume 32, pages 3443–3451 (2013)Cite this article

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Abstract

Amplification and overexpression of the receptor tyrosine kinase ErbB2 occur in up to 30% of human breast cancers, and high ErbB2 levels are correlated with poor prognosis for breast cancer patients. In contrast to the epithelial growth factor receptor (ErbB1), ErbB2 is not downregulated by ligand-induced mechanisms. Here we show that flotillins are involved in the stabilization of ErbB2 at the plasma membrane. In SKBR3 breast cancer cells and breast cancer tissue, a positive correlation between flotillin and ErbB2 expression levels could be demonstrated. Moreover, the tissue microarray analyses of biopsies from 194 patients diagnosed with carcinomas of the breast showed that flotillin-2 emerged as a potential predictor of prognosis in breast cancer. Depletion of flotillin-1 and flotillin-2 leads to internalization and degradation of ErbB2. Furthermore, flotillin-1 and -2 were found to be in a molecular complex with ErbB2 and Hsp90. The depletion of one of these proteins results in disruption of this complex, followed by destabilization of ErbB2 at the membrane, and its internalization and degradation. As a consequence, ErbB2-triggered downstream signalling is inhibited. Our data demonstrate a novel mechanism for interfering with ErbB2 signalling, which potentially can have clinical impact.

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Acknowledgements

We thank Wanja Kildal, Anne-Mari Gjestvang Pedersen and Anne Engen for their expert technical assistance. We thank Gisou van der Goot (EPFL, Lausanne, Switzerland) for providing the polyclonal flotillin-1 antibody used in confocal microscopy. We thank Ørnulf Borgan for assistance with the analysis of the results from the breast tissue samples. We thank the South-Eastern Norway Regional Health Authority (Helse Sør-Øst), the Norwegian Research Council and the Norwegian Cancer Society for financial support.

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Authors and Affiliations

  1. Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    S Pust, T I Klokk, N Musa, L Tcatchoff & K Sandvig

  2. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    S Pust, T I Klokk, N Musa, M Jenstad, B Risberg, L Tcatchoff, K Liestøl, H E Danielsen & K Sandvig

  3. Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway

    M Jenstad, B Risberg & H E Danielsen

  4. Department of Pathology, Oslo University Hospital, Oslo, Norway

    B Risberg

  5. Oslo University Hospital, Oslo, Norway

    B Erikstein

  6. Department of Cellular and Molecular Medicine, The Panum Building, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    B van Deurs

  7. Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway

    K Sandvig

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Pust, S., Klokk, T., Musa, N. et al. Flotillins as regulators of ErbB2 levels in breast cancer. Oncogene 32, 3443–3451 (2013). https://doi.org/10.1038/onc.2012.357

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