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Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells

Oncogene volume 21, pages 4567–4576 (2002)Cite this article

Abstract

Addition of the ErbB-ligand, Heregulinβ1 (HRG), to breast tumour-derived T47D cells promotes D-cyclin expression, p21cip1 synthesis, cyclin-dependent kinase (CDK) activation through re-distribution of p27kip1 and DNA synthesis. In contrast EGF has no effect on T47D cell cycle progression. By comparing these two ligands and the use of specific inhibitors for phosphatidylinositol-3 kinase (PI3K), mitogen-activated protein kinase (MAPK) and p38MAPK, we have identified several molecular mechanisms required for ErbB receptor-mediated proliferation. The PI3K, MAPK and p38MAPK pathways each displayed distinct activation profiles in response to either HRG or EGF, with obvious differences in both the intensity and duration of signal output. Through inhibition of each of these pathways it is apparent that each pathway is necessary, yet insufficient alone, to stimulate proliferation. Each pathway regulates distinct subsets of essential cell cycle regulators and integration of these signal networks is required for the timely expression of these components, which culminates in cell cycle progression. Significantly, the mechanisms controlling ligand-stimulated proliferation through ErbB2 are strikingly similar to the mechanisms through which overexpressed, constitutively activated, ErbB2 orchestrates uncontrolled proliferation in cancer cells. This suggests that downstream effectors of ErbB receptors represent good therapeutic targets for breast cancer.

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Acknowledgements

Richard Neve was partially supported by a grant from the Krebsliga beider Basel. Thomas Holbro acknowledges a grant from the Novartis Stiftung fuer medizinisch-biologische Forschung and the Krebsliga beider Basel. We wish to thank Nicholas Pullen, Chris Benz, Hema Parmar, Ali Badache and Sinisa Volarevic for helpful discussions and reagents, and Novartis as a sponsor of the FMI.

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  1. Richard M Neve and Thomas Holbro: RM Neve and T Holbro contributed equally to this work

Authors and Affiliations

  1. Novartis Forschungsstiftung Zweigniederlassung Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Thomas Holbro & Nancy E Hynes

  2. Department of Hematology/Oncology, UCSF San Francisco and Buck Institute, Novato, 94945, California, CA, USA

    Richard M Neve

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  1. Richard M Neve
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Correspondence to Richard M Neve.

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Neve, R., Holbro, T. & Hynes, N. Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells. Oncogene 21, 4567–4576 (2002). https://doi.org/10.1038/sj.onc.1205555

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