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Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines

Oncogene volume 22, pages 8063–8071 (2003)Cite this article

Abstract

The rapid cell cycle arrest in response to DNA damage is mediated by degradation of the Cdc25A phosphatase, a proto-oncogene whose mRNA is frequently overexpressed in human tumours. Here, we study the occurrence and mechanisms of Cdc25A deregulation in human breast cancer cell lines. We demonstrate aberrantly elevated Cdc25A protein abundance and phosphatase activity in eight out of 15 cell lines, in some cases resulting in abrogation of the Cdc25A-mediated checkpoint response to ionizing radiation (IR), and this defect correlated with hypersensitivity to IR. Furthermore, we present evidence that deregulation of Cdc25A occurs predominantly on the post-transcriptional level, as overabundant Cdc25A protein was usually not accompanied by adequate mRNA overexpression. Instead, we demonstrate that aberrantly enhanced protein stability is an important mechanism underlying Cdc25A overabundance in a subset of breast cancer cell lines. Given the frequency of this mechanism, we propose that the DNA integrity checkpoint controlling Cdc25A protein stability might be a common target for deregulation in breast cancer.

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Acknowledgements

We thank P Guldberg for help with the real-time PCR, AE Lykkesfeldt and PE Lønning for some of the cell lines, and current and former members of the Department of Cell Cycle and Cancer for generously sharing expertise and ideas. This work was supported by the Danish Cancer Society, the European Commission, the Dr Mildred Scheel Stiftung für Krebsforschung, Bonn, Germany, the Danish Medical Research Council, and the Alfred Benzon's Fund.

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  1. Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Harald Löffler, Randi G Syljuåsen, Jirina Bartkova, Jesper Worm, Jiri Lukas & Jiri Bartek

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  1. Harald Löffler
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  2. Randi G Syljuåsen
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  3. Jirina Bartkova
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Correspondence to Jiri Bartek.

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Löffler, H., Syljuåsen, R., Bartkova, J. et al. Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines. Oncogene 22, 8063–8071 (2003). https://doi.org/10.1038/sj.onc.1206976

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