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The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours

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Summary

The serine–threonine protein phosphatase PPM1D is likely to play an important role in tumorigenesis. Through inactivation of p38 MAPK, PPM1D acts as a negative feedback regulator of p53 tumour suppressor gene and controls the expression of other cell cycle regulatory proteins, such as CCND1. In addition, recent knock-out mouse studies implicated PPM1D in the regulation of p16 expression and the RB tumour suppressor pathway. Here we explored the role of PPM1D aberrations in primary breast cancer. PPM1D copy number analysis showed amplification in 11% (13/117) of the tumours and quantitative real-time RT-PCR revealed a significant correlation (p=0.0148) between PPM1D amplification and increased expression. PPM1D amplification occurred almost exclusively in tumours with wild-type p53 suggesting that these events are mutually exclusive and further confirming the role of PPM1D as a negative regulator of p53. Interestingly, PPM1D amplification was associated with ERBB2 expression (p=0.0001) thus implying that PPM1D aberrations occurs in tumours with poor prognosis. We also explored the expression levels of two possible downstream targets of PPM1D. However, immunohistochemical analyses revealed no differences in the staining patterns of CCND1 and p16 proteins in tumours with or without PPM1D aberrations, thus suggesting that previous data from animal model experiments is not directly transferable to primary human tumours. On the other hand, these key cellular proteins are likely to be regulated through a complex fashion in breast cancer and apparently PPM1D represents only one of these mechanisms. Taken together, our findings substantiate an important role for PPM1D in breast cancer.

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Abbreviations

FISH:

fluorescence in situ hybridisation

RT-PCR:

reverse transcription-PCR

TMA:

tissue microarray

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Acknowledgements

We would like to thank Ms Kati Rouhento and Ms Reija Randen for excellent technical assistance. This work was partly supported by the Academy of Finland, the Medical Research Fund of the Tampere University Hospital, Pirkanmaa Cultural Foundation, as well as Maud Kuistila Foundation.

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Authors and Affiliations

  1. Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

    Jenita Rauta, Emma-Leena Alarmo, Päivikki Kauraniemi, Ritva Karhu & Anne Kallioniemi

  2. Department of Pathology, University of Tampere and Tampere University Hospital, Tampere, Finland

    Tuula Kuukasjärvi

  3. Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, 33014, Tampere, Finland

    Anne Kallioniemi

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  1. Jenita Rauta
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  2. Emma-Leena Alarmo
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  3. Päivikki Kauraniemi
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  5. Tuula Kuukasjärvi
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  6. Anne Kallioniemi
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Correspondence to Anne Kallioniemi.

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Address for offprints and correspondence: Prof A. Kallioniemi, Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere, Tampere 33014, Finland; Tel.: +358-3-311 64125, Fax: +358-3-311 74168; E-mail: anne.kallioniemi@uta.fi

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Rauta, J., Alarmo, EL., Kauraniemi, P. et al. The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Res Treat 95, 257–263 (2006). https://doi.org/10.1007/s10549-005-9017-7

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  • DOI: https://doi.org/10.1007/s10549-005-9017-7

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