Breast Cancer Research and Treatment

, Volume 95, Issue 3, pp 257–263

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

  • Jenita Rauta
  • Emma-Leena Alarmo
  • Päivikki Kauraniemi
  • Ritva Karhu
  • Tuula Kuukasjärvi
  • Anne Kallioniemi
Preclinical study

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.

Keywords

breast cancer gene amplification p53 PPM1D protein phosphatase 

Abbreviations

FISH

fluorescence in situ hybridisation

RT-PCR

reverse transcription-PCR

TMA

tissue microarray

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References

  1. 1.
    Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O’Connor PM, Appella E, 1997 Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner Proc Natl Acad Sci USA 94: 6048–6053CrossRefPubMedGoogle Scholar
  2. 2.
    Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H, Taya Y, Imai K, 2000 p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation EMBO J 19: 6517–6526CrossRefPubMedGoogle Scholar
  3. 3.
    Lavoie JN, L’Allemain G, Brunet A, Muller R, Pouyssegur J, 1996 Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway J Biol Chem 271: 20608–20616CrossRefPubMedGoogle Scholar
  4. 4.
    Bulavin DV, Higashimoto Y, Popoff IJ, Gaarde WA, Basrur V, Potapova O, Appella E, Fornace AJ Jr, 2001 Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase Nature 411: 102–107CrossRefPubMedGoogle Scholar
  5. 5.
    Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, Ambrosino C, Sauter G, Nebreda AR, Anderson CW, Kallioniemi A, Fornace AJ,Jr, Appella E, 2002 Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity Nat Genet 31: 210–215CrossRefPubMedGoogle Scholar
  6. 6.
    Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven WG, Nguyen KC, Gabriele T, McCurrach ME, Marks JR, Hoey T, Lowe SW, Powers S, 2002 Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23 Nat Genet 31: 133–134CrossRefPubMedGoogle Scholar
  7. 7.
    Saito-Ohara F, Imoto I, Inoue J, Hosoi H, Nakagawara A, Sugimoto T, Inazawa J, 2003 PPM1D is a potential target for 17q gain in neuroblastoma Cancer Res 63: 1876–1883PubMedGoogle Scholar
  8. 8.
    Lu X, Nguyen TA, Appella E, Donehower LA, 2004 Homeostatic regulation of base excision repair by a p53-induced phosphatase: linking stress response pathways with DNA repair proteins Cell Cycle 3: 1363–1366PubMedGoogle Scholar
  9. 9.
    Choi J, Nannenga B, Demidov ON, Bulavin DV, Cooney A, Brayton C, Zhang Y, Mbawuike IN, Bradley A, Appella E, Donehower LA, 2002 Mice deficient for the wild-type p53-induced phosphatase gene (Wip1) exhibit defects in reproductive organs, immune function, and cell cycle control Mol Cell Biol 22: 1094–1105CrossRefPubMedGoogle Scholar
  10. 10.
    Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, Appella E, Fornace AJ Jr, 2004 Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(arf) pathway Nat Genet 36: 343–350CrossRefPubMedGoogle Scholar
  11. 11.
    Andersen CL, Monni O, Wagner U, Kononen J, Barlund M, Bucher C, Haas P, Nocito A, Bissig H, Sauter G, Kallioniemi A, 2002 High-throughput copy number analysis of 17q23 in 3520 tissue specimens by fluorescence in situ hybridization to tissue microarrays Am J Pathol 161: 73–79PubMedGoogle Scholar
  12. 12.
    Sinclair CS, Rowley M, Naderi A, Couch FJ, 2003 The 17q23 amplicon and breast cancer Breast Cancer Res Treat 78: 313–322CrossRefPubMedGoogle Scholar
  13. 13.
    Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T, Nozawa S, Inazawa J, Imoto I, 2003 Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets Clin Cancer Res 9: 1995–2004PubMedGoogle Scholar
  14. 14.
    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP, 1998 Tissue microarrays for high-throughput molecular profiling of tumor specimens Nat Med 4: 844–847CrossRefPubMedGoogle Scholar
  15. 15.
    Andersen CL, Hostetter G, Grigoryan A, Sauter G, Kallioniemi A, 2001 Improved procedure for fluorescence in situ hybridization on tissue microarrays Cytometry 45: 83–86CrossRefPubMedGoogle Scholar
  16. 16.
    Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, Paavola P, Avela K, Chen Y, Bittner ML, Kallioniemi A, 2001 Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer Proc Natl Acad Sci USA 98: 5711–5716CrossRefPubMedGoogle Scholar
  17. 17.
    Ross JS, Fletcher JA, 1999 The HER-2/neu oncogene: prognostic factor, predictive factor and target for therapy Semin Cancer Biol 9: 125–138CrossRefPubMedGoogle Scholar
  18. 18.
    Bärlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G, Kallioniemi OP, Kallioniemi A, 2000 Multiple genes at 17q23 undergo amplification and overexpression in breast cancer Cancer Res 60: 5340–5344PubMedGoogle Scholar
  19. 19.
    Hyman E, Kauraniemi P, Hautaniemi S, Wolf M, Mousses S, Rozenblum E, Ringner M, Sauter G, Monni O, Elkahloun A, Kallioniemi OP, Kallioniemi A, 2002 Impact of DNA amplification on gene expression patterns in breast cancer Cancer Res 62: 6240–6245PubMedGoogle Scholar
  20. 20.
    Orsetti B, Nugoli M, Cervera N, Lasorsa L, Chuchana P, Ursule L, Nguyen C, Redon R, du Manoir S, Rodriguez C, Theillet C, 2004 Genomic and expression profiling of chromosome 17 in breast cancer reveals complex patterns of alterations and novel candidate genes Cancer Res 64: 6453–6460CrossRefPubMedGoogle Scholar
  21. 21.
    Rennstam K, Ahlstedt-Soini M, Baldetorp B, Bendahl PO, Borg A, Karhu R, Tanner M, Tirkkonen M, Isola J, 2003 Patterns of chromosomal imbalances defines subgroups of breast cancer with distinct clinical features and prognosis. A study of 305 tumors by comparative genomic hybridization. Cancer Res 63: 8861–8868PubMedGoogle Scholar
  22. 22.
    Borresen-Dale AL, 2003 TP53 and breast cancer Hum Mutat 21: 292–300CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Jenita Rauta
    • 1
  • Emma-Leena Alarmo
    • 1
  • Päivikki Kauraniemi
    • 1
  • Ritva Karhu
    • 1
  • Tuula Kuukasjärvi
    • 2
  • Anne Kallioniemi
    • 1
    • 3
  1. 1.Laboratory of Cancer Genetics, Institute of Medical TechnologyUniversity of Tampere and Tampere University HospitalTampereFinland
  2. 2.Department of PathologyUniversity of Tampere and Tampere University HospitalTampereFinland
  3. 3.Laboratory of Cancer Genetics, Institute of Medical TechnologyUniversity of Tampere and Tampere University HospitalTampereFinland

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