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Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells

Oncogene volume 21, pages 6573–6586 (2002)Cite this article

Abstract

Most breast cancers arise from luminal epithelial cells and 25–30% of these tumours overexpress the ErbB-2 receptor. Herein, a non-transformed, immortalized cell system was used to investigate the effects of ErbB-2 overexpression in luminal epithelial cells. The phenotypic consequence of ErbB-2 overexpression is a shortening of the G1 phase of the cell cycle and early S phase entry, which leads to hyperproliferation. We show that this effect was mediated through the up-regulation of cdk6 and cyclins D1 and E, and enhanced degradation and relocalization of p27Kip1. These changes were effected predominantly through enhanced MAPK signalling, resulting in cdk2 hyperactivation. PI3K signalling also participated in cell cycle progression, since PI3K and MAPK coordinately regulated changes in cyclin D1 and cdk6 expression. Cdk4 activity was not required for cell cycle progression in these cells, and was constitutively inhibited through its association with p16INK4A. MAPK-dependent induction of p21Cip1 was also necessary for G1 phase progression, although its degradation by the proteasome was required for S phase entry. These data provide new insights into the complex molecular mechanisms underlying mitogenic cell cycle control in luminal epithelial cells, the cell type relevant to primary breast cancer, and show how ErbB-2 overexpression subverts this normal control.

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Acknowledgements

We would like to thank Drs Parmjit Jat and Karin Barnouin for critical reading of the manuscript. We are also grateful to Drs Eric Lam, Gordon Peters, Peter Elliot, Julian Adams and Julian Downward for providing reagents.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, 91 Riding House Street, London, W1W 7BS, UK

    John F Timms, Sarah L White, Michael J O'Hare & Michael D Waterfield

  2. Department of Surgery, University College London Breast Cancer Laboratory, Royal Free and University College Medical School, Charles Bell House, 67–73 Riding House Street, London, W1W 7EJ, UK

    Michael J O'Hare

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  1. John F Timms
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Correspondence to John F Timms.

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Timms, J., White, S., O'Hare, M. et al. Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. Oncogene 21, 6573–6586 (2002). https://doi.org/10.1038/sj.onc.1205847

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