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Polo-like kinase isoforms in breast cancer: expression patterns and prognostic implications

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Abstract

Polo-like kinase (PLK) family members are known to be functionally involved in mitotic signaling and in cytoskeletal reorganization in both normal and malignant cells. In this study, expression of PLK1 and PLK3 was determined immunohistochemically in tissue specimens of 135 breast carcinomas, and expression was correlated with clinicopathological parameters and patient prognosis. Strong PLK isoform overexpression was observed in 42.2% (PLK1) and 47.4% (PLK3) of breast carcinomas when compared with non-transformed breast tissue. A positive correlation of PLK isoform expression with tumor grade, vascular invasion, erbB2/HER-2 expression and markers of proliferative activity was evident. Additionally, an inverse correlation of PLK isoform expression and estrogen receptor status was observed. Overexpression of PLK3 but not of PLK1 was significantly linked to reduced median overall (P<0.001) and relapse-free (P=0.021) survival time. PLK3 expression remained an independent prognostic factor for overall (RR=3.2, P=0.002) and relapse-free (RR=2.9, P=0.049) survival in multivariate survival analysis. These results suggest PLK3 as a novel independent prognostic marker in breast cancer and hint toward a role for PLK isoform overexpression in disease progression. Therefore, in vivo inhibition of PLK family members might represent a rewarding approach in the development of new anticancer drugs for this tumor entity.

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References

  1. Bahassi el M, Conn CW, Myer DL, Hennigan RF, McGowan CH, Sanchez Y, Stambrook PJ (2002) Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene 21:6633–6640

    Google Scholar 

  2. Barr FA, Sillje HH, Nigg EA (2004) Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5:429–440

    Google Scholar 

  3. Bertz J, Hentschel S, Hundsdörfer G, Kaatsch P, Katalinic A, Lehnert M Schön D, Stegmaier C, Ziegler H (2004) Krebs in Deutschland. 4. überarbeitete, aktualisierte Ausgabe. Arbeitsgemeinschaft Bevölkerungsbezogener Krebsregister in Deutschland, Saarbrücken

  4. Chase D, Feng Y, Hanshew B, Winkles JA, Longo DL, Ferris DK (1998) Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression. Biochem J 333:655–660

    Google Scholar 

  5. Dai W, Wang Q, Traganos F (2002) Polo-like kinases and centrosome regulation. Oncogene 21:6195–6200

    Google Scholar 

  6. Dietzmann K, Kirches E, von Bossanyi P, Jachau K, Mawrin C (2001) Increased human polo-like kinase-1 expression in gliomas. J Neuro-Oncol 53:1–11

    Google Scholar 

  7. Donaldson MM, Tavares AA, Hagan IM, Nigg EA, Glover DM (2001) The mitotic roles of Polo-like kinase. J Cell Sci 114:2357–2358

    Google Scholar 

  8. Elez R, Piiper A, Kronenberger B, Kock M, Brendel M, Hermann E, Pliquett U, Neumann E, Zeuzem S (2003) Tumor regression by combination antisense therapy against Plk1 and Bcl-2. Oncogene 22:69–80

    Google Scholar 

  9. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 5:403–410

    Google Scholar 

  10. Golan A, Yudkovsky Y, Hershko A (2002) The cyclin–ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk. J Biol Chem 277:15552–15557

    Google Scholar 

  11. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2003) Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357–3365

    Article  PubMed  Google Scholar 

  12. Holtrich U, Wolf G, Yuan J, Bereiter-Hahn J, Karn T, Weiler M, Kauselmann G, Rehli M, Andreesen R, Kaufmann M, Kuhl D, Strebhardt K (2000) Adhesion induced expression of the serine/threonine kinase Fnk in human macrophages. Oncogene 19:4832–4839

    Google Scholar 

  13. Ito Y, Miyoshi E, Sasaki N, Kakudo K, Yoshida H, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Matsuura N, Kuma K, Miyauchi A (2004) Polo-like kinase 1 overexpression is an early event in the progression of papillary carcinoma. Br J Cancer 90:414–418

    Google Scholar 

  14. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ; American Cancer Society (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29

    PubMed  Google Scholar 

  15. Jensen EV, Cheng G, Palmieri C, Saji S, Makela S, Van Noorden S, Wahlstrom T, Warner M, Coombes RC, Gustafsson JA (2001) Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci U S A 98:15197–15202

    Google Scholar 

  16. Kauselmann G, Weiler M, Wulff P, Jessberger S, Konietzko U, Scafidi J, Staubli U, Bereiter-Hahn J, Strebhardt K, Kuhl D (1999) The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J 18:5528–5539

    Article  Google Scholar 

  17. Knecht R, Elez R, Oechler M, Solbach C, von Ilberg C, Strebhardt K (1999) Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res 59:2794–2797

    Google Scholar 

  18. Kneisel L, Strebhardt K, Bernd A, Wolter M, Binder A, Kaufmann R (2002) Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease. J Cutan Pathol 29:354–358

    Google Scholar 

  19. Lee M, Daniels MJ, Venkitaraman AR (2004) Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression. Oncogene 23:865–872

    Google Scholar 

  20. Liu X, Erikson RL (2003) Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 100:5789–5794

    Google Scholar 

  21. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  CAS  PubMed  Google Scholar 

  22. Nicholson RI, McClelland RA, Robertson JF, Gee JM (1999) Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer. Endocr Relat Cancer 6:373–387

    Google Scholar 

  23. Nigg EA (1998) Polo-like kinases: positive regulators of cell division from start to finish. Curr Opin Cell Biol 10:776–783

    Google Scholar 

  24. Ouyang B, Pan H, Lu L, Li J, Stambrook P, Li B, Dai W (1997) Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J Biol Chem 272:28646–28651

    Google Scholar 

  25. Spänkuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K (2002) Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 94:1863–1877

    Google Scholar 

  26. Spyratos F, Ferrero-Pous M, Trassard M, Hacene K, Phillips E, Tubiana-Hulin M, Le Doussal V (2002) Correlation between MIB-1 and other proliferation markers: clinical implications of the MIB-1 cutoff value. Cancer 94:2151–2159

    Article  CAS  PubMed  Google Scholar 

  27. Sumara I, Vorlaufer E, Stukenberg PT, Kelm O, Redemann N, Nigg EA, Peters JM (2002) The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase. Mol Cell 9:515–525

    Article  CAS  PubMed  Google Scholar 

  28. Sunkel CE, Glover DM (1988) Polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J Cell Sci 89:25–38

    Google Scholar 

  29. Takahashi T, Sano B, Nagata T, Kato H, Sugiyama Y, Kunieda K, Kimura M, Okano Y, Saji S (2003) Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers. Cancer Sci 94:148–152

    Google Scholar 

  30. Tirkkonen M, Tanner M, Karhu R, Kallioniemi A, Isola J, Kallioniemi OP (1998) Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosomes Cancer 21:177–184

    Google Scholar 

  31. Tokumitsu Y, Mori M, Tanaka S, Akazawa K, Nakano S, Niho Y (1999) Prognostic significance of polo-like kinase expression in esophageal carcinoma. Int J Oncol 15:687–692

    Google Scholar 

  32. Toyoshima-Morimoto F, Taniguchi E, Nishida E (2002) Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep 3:341–348

    Google Scholar 

  33. Volpi A, Nanni O, De Paola F, Granato AM, Mangia A, Monti F, Schittulli F, De Lena M, Scarpi E, Rosetti P, Monti M, Gianni L, Amadori D, Paradiso A (2003) HER-2 expression and cell proliferation: prognostic markers in patients with node-negative breast cancer. J Clin Oncol 21:2708–2712

    Google Scholar 

  34. Wang Q, Xie S, Chen J, Fukasawa K, Naik U, Traganos F, Darzynkiewicz Z, Jhanwar-Uniyal M, Dai W (2002) Cell cycle arrest and apoptosis induced by human Polo-like kinase 3 is mediated through perturbation of microtubule integrity. Mol Cell Biol 22:3450–3459

    Google Scholar 

  35. Weichert W, Denkert C, Schmidt M, Gekeler V, Wolf G, Köbel M, Dietel M, Hauptmann S (2004) Polo like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 90:815–821

    Google Scholar 

  36. Weichert W, Schmidt M, Gekeler V, Bellach J, Denkert C, Stephan C, Jung K, Loening S, Dietel M, Kristiansen G (2004) Polo like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades. Prostate 60:240–245

    Google Scholar 

  37. Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, Altmannsberger HM, Rubsamen-Waigmann H, Strebhardt K (1997) Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 14:543–549

    Google Scholar 

  38. Wolf G, Hildenbrand R, Schwar C, Grobholz R, Kaufmann M, Stutte HJ, Strebhardt K, Bleyl U (2000) Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer. Pathol Res Pract 196:753–759

    Google Scholar 

  39. Yamada S, Ohira M, Horie H, Ando K, Takayasu H, Suzuki Y, Sugano S, Hirata T, Goto T, Matsunaga T, Hiyama E, Hayashi Y, Ando H, Suita S, Kaneko M, Sasaki F, Hashizume K, Ohnuma N, Nakagawara A (2004) Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene 23:5901–5911

    Google Scholar 

  40. Yuan J, Eckerdt F, Bereiter-Hahn J, Kurunci-Csacsko E, Kaufmann M, Strebhardt K (2002) Cooperative phosphorylation including the activity of polo-like kinase 1 regulates the subcellular localization of cyclin B1. Oncogene 21:8282–8292

    Google Scholar 

  41. Zhou BP, Hung MC (2003) Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin Oncol 30:38–48

    Google Scholar 

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Acknowledgements

We are grateful to Lisa Glanz for excellent technical assistance and Martina Eickmann for critical reading and help in the preparation of the manuscript.

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Authors and Affiliations

  1. Institute of Pathology, Charité University Hospital, Schumannstraße 20/21, 10117, Berlin, Germany

    Wilko Weichert, Glen Kristiansen, Aurelia Noske, Berit-Maria Müller, Silvia Niesporek, Manfred Dietel & Carsten Denkert

  2. Breast Center, Charité University Hospital, Berlin, Germany

    Klaus-Jürgen Winzer

  3. Altana Pharma AG, Konstanz, Germany

    Mathias Schmidt & Volker Gekeler

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  1. Wilko Weichert
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Correspondence to Wilko Weichert.

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Weichert, W., Kristiansen, G., Winzer, KJ. et al. Polo-like kinase isoforms in breast cancer: expression patterns and prognostic implications. Virchows Arch 446, 442–450 (2005). https://doi.org/10.1007/s00428-005-1212-8

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  • DOI: https://doi.org/10.1007/s00428-005-1212-8

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