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Activation of the α2β1 integrin prevents c-erbB2-induced scattering and apoptosis of human mammary epithelial cells in collagen

Oncogene volume 19, pages 4592–4603 (2000)Cite this article

Abstract

Constitutive overexpression of c-erbB2 in the mammary epithelial cell line MTSV1-7 has been shown to result in epithelial-mesenchymal conversion, anchorage-independent growth and loss of organized morphogenesis in collagen. To elucidate the events leading to this drastic change, MTSV1-7 cells and its subclone HB2 (which shows a more strictly epithelial phenotype) were transfected with the hybrid trk-neu receptor consisting of the extracellular domain of the trkA nerve growth factor (NGF) receptor and the transmembrane and cytoplasmic domains of c-erbB2 (neu). In cells expressing this construct, c-erbB2 homodimerization can be mimicked by addition of NGF. In trk-neu transfectants of HB2 cells, modest expression led to increased cell proliferation upon NGF treatment. When clones with higher expression levels were grown in collagen, NGF instead induced cell scattering, diminished viability and dramatically increased apoptosis. Interestingly, both the dissociation of colonies and loss of cell viability could be completely reversed by treatment of the cells with antibodies that activate the adhesive capacity of the α2β1 integrin. Long-term NGF treatment of high-expressing transfectants generated fibroblastic clones displaying a reduced expression of integrin α2 and E-cadherin, and extensive apoptosis in collagen. These results, which indicate that strong c-erbB2 signalling may lead to downregulation and/or inactivation of the α2β1 integrin, promoting apoptosis in collagen, provide one possible explanation to the increased apoptosis frequently seen in early tumour development.

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Acknowledgements

The authors thank Dr Martin Sachs and Prof Walter Birchmeier for the gift of the pBAT/trk-neu plasmid and Dr Fiona Watt for supplying the HAS4 antibody. The P5D2 hybridoma developed by EA Wayner was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa. This work was supported by Assar Gabrielsson's Fund, the Swedish Cancer Fund (grant no. 975098), the Imperial Cancer Research Fund and the European Commission (fellowship grants no. ERBCHBGCT 94-0556 and ERB4001GT965003).

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  1. Department of Medical Biochemistry, University of Göteborg, Box 440, SE-405 30 Göteborg, Sweden

    Dan Baeckström

  2. Breast Cancer Biology Laboratory, Imperial Cancer Research Fund, 3rd Floor, Thomas Guy House, Guy's Hospital, London, SE1 9RT, UK

    Pei-Juan Lu & Joyce Taylor-Papadimitriou

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Baeckström, D., Lu, PJ. & Taylor-Papadimitriou, J. Activation of the α2β1 integrin prevents c-erbB2-induced scattering and apoptosis of human mammary epithelial cells in collagen. Oncogene 19, 4592–4603 (2000). https://doi.org/10.1038/sj.onc.1203792

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