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Predictive and prognostic values of Tau and BubR1 protein in prostate cancer and their relationship to the Gleason score

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Abstract

The aim of this study is to detect the expression levels of spindle assembly checkpoint protein-BubR1 and microtubule-associated protein-Tau in human prostate cancer tissues of different Gleason score, and to test whether there is a relationship between their expression levels and clinicopathologic parameters including response to docetaxel treatment, Gleason score, and overall survival (OS). Moreover, to test whether Tau protein expressed in the cancerous prostate tissue is phosphorylated. Thirty patients who received at least three cycles docetaxel for metastatic castrate-resistant prostate cancer were included into the trial. The patients’ formalin-fixed and paraffin-embedded prostate tissue specimens were retrospectively obtained from the pathology department archives of Ege University School of Medicine. The expression status of BubR1 protein was defined by immunohistochemical (IHC) using the anti-BubR1 antibody. The expression status of Tau protein was defined by IHC using the two types of Tau antibodies: anti-Tau-1 antibody (that recognizes Tau only in its dephosphorylated form) and anti-PHF-Tau antibody (that recognizes all isoforms of human Tau proteins independent of its phosphorylation status). The BubR1 and Tau were overexpressed in about 63 and 23 % of the study group, respectively. Tau overexpression was significantly associated with lower Gleason score. There was no significant association between the expression levels of BubR1 and Tau proteins, and docetaxel response. Reduced BubR1 expression was strongly associated with longer survival (P = 0.008), whereas Tau expression status did not effect survival. Moreover, the Tau expression of cancerous prostate tissue was highly dephosphorylated. In this clinicopathological study, our findings did not confirm the preclinical observations that low BubR1 and Tau expression confer selective sensitivity to microtubulisin drugs. Our data imply that reduced BubR1 expression was a predictor for longer OS, and the possibility that high Tau expression may be involved in better prognosis due to its relationship to the Gleason score. Furthermore, our data suggest that both Tau and BubR1 may be a promising prognostic marker rather than predictive marker in patients with prostate cancer.

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Abbreviations

Bub1-3:

Budding uninhibited by benzimidazoles

BubR1:

Budding uninhibited by benzimidazoles 1-related protein kinase

IHC:

Immunohistochemical

mCRPC:

Metastatic castrate-resistant prostate cancer

RECIST:

Response evaluation criteria in solid tumors

PSA:

Prostate-specific antigen

MAPs:

Microtubule-associated proteins

SAC:

Spindle assembly checkpoint

Mad1–3:

Mitotic arrest deficient proteins

OS:

Overall survival

DFS:

Disease-free survival

FFS:

Recurrence-free survival

HR:

Hazard ratio

NSABP:

National surgical breast and bowel project

ER:

Estrogen receptor

HER2:

Epidermal growth factor receptor 2

References

  1. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20.

    Article  PubMed  CAS  Google Scholar 

  2. Tannock IF, de Wit R, Horti J, et al. Docetaxel plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.

    Article  PubMed  CAS  Google Scholar 

  3. McGrogan BT, Gilmartin B, Carney DN, McCann A. Taxanes, microtubules and chemo resistant breast cancer. Biochim Biophys Acta. 2008;1785:96–132.

    PubMed  CAS  Google Scholar 

  4. Orr G, Verdier PP. Mechanisms of taxol resistance related to microtubules. Oncogene. 2003;22:7280–95.

    Article  PubMed  CAS  Google Scholar 

  5. Honore S, Pasquier E, Braguer D. Understanding microtubule dynamics for improved cancer therapy. Cell Mol Life Sci. 2005;62:3039–56.

    Article  PubMed  CAS  Google Scholar 

  6. Dehmelt L, Halpain S. The MAP2/tau family of microtubule-associated Proteins. Genome Biol. 2004;6:204.

    Article  PubMed  Google Scholar 

  7. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93.

    Article  PubMed  CAS  Google Scholar 

  8. Rouzier R, Rajan R, Wagnera P, et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci USA. 2005;102:8315–20.

    Article  PubMed  CAS  Google Scholar 

  9. Munro A, Cameron D, Thomas J, Twelves C, Bartlett J. BUBR1 and MAD2: novel markers for predicting benefit from adjuvant anthracyclines? abstracts: thirty-second annual ctrc-aacr san antonio breast cancer symposium 2009; San Antonio. J Cancer Res. 2009;69(4):2124.

    Article  Google Scholar 

  10. Rizzardi C, Torelli L, Barresi E, et al. Bubr1 expression in oral squamous cell carcinoma and its relationship to tumor stage and survival. Head Neck. 2011;33(5):727–33.

    Article  PubMed  Google Scholar 

  11. Lee YK, Choi E, Kim MA, Park PG, Park NH, Lee H. BubR1 as a prognostic marker for recurrence-free survival rates in epithelial ovarian cancers. Br J Cancer. 2009;101(3):504–10.

    Article  PubMed  CAS  Google Scholar 

  12. Shao YY, Kuo KT, Hu FC, et al. Predictive and prognostic values of tau and ERCC1 in advanced breast cancer patients treated with paclitaxel and cisplatin. J Clin Oncol. 2009;27(26):4287–92.

    Article  Google Scholar 

  13. Pusztai L, Jeong JH, Gong Y, et al. Evaluation of microtubule-associated protein-Tau expression as a prognostic and predictive marker in the NSABP-B 28 randomized clinical trial. J Clin Oncol. 2009;27(26):4287–92.

    Article  PubMed  CAS  Google Scholar 

  14. Souter S, Lee G. Microtubule-associated protein tau in human prostate cancer cells: isoforms, phosphorylation, and interactions. J Cell Biochem. 2009;108(3):555–64.

    Article  PubMed  CAS  Google Scholar 

  15. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the prostate-specific antigen working group. J Clin Oncol. 1999;17:3461–7.

    PubMed  CAS  Google Scholar 

  16. Scher HI, Halabi S, Tannock I, et al. Prostate cancer clinical trials working group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical TrialsWorking Group. J Clin Oncol. 2008;26:1148–59.

    Article  PubMed  Google Scholar 

  17. Nagao K, Yamamoto Y, Hara T, et al. Ki67 and BUBR1 May discriminate clinically insignificant prostate cancer in the PSA Range <4 ng/ml. Jpn J Clin Oncol. 2011;41(4):555–64.

    Article  PubMed  Google Scholar 

  18. Noguchi S. Predictive factors for response to docetaxel in human breast cancers. Cancer Sci. 2006;97:813–20.

    Article  PubMed  CAS  Google Scholar 

  19. Sudo T, Nitta M, Saya H, Ueno NT. Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res. 2004;64:2502–8.

    Article  PubMed  CAS  Google Scholar 

  20. Cheung HW, Jin DY, Ling MT, et al. Mitotic arrest deficient 2 expression induces chemo sensitization to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res. 2005;65:1450–8.

    Article  PubMed  CAS  Google Scholar 

  21. Nitta M, Kobayashi O, Honda S, et al. Spindle checkpoint function is required for mitotic catastrophe induced by DNA damaging agents. Oncogene. 2004;23:6548–58.

    Article  PubMed  CAS  Google Scholar 

  22. Vogel C, Kienitz A, Muller R, Bastians H. The mitotic spindle checkpoint is a critical determinant for topoisomerase-based chemotherapy. J Biol Chem. 2005;280:4025–8.

    Article  PubMed  CAS  Google Scholar 

  23. Fang Y, Liu T, Wang X, et al. BubR1 is involved in regulation of DNA damage responses. Oncogene. 2006;25(25):3598–605.

    Article  PubMed  CAS  Google Scholar 

  24. Lee EA, Keutmann MK, Dowling ML, Harris E, Chan G, Kao GD. Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells. Mol Cancer Ther. 2004;3:661–9.

    PubMed  CAS  Google Scholar 

  25. Seike M, Gemma A, Hosoya Y, et al. The promoter region of the human BUBR1 gene and its expression analysis in lung cancer. Lung Cancer. 2002;38:229–34.

    Article  PubMed  Google Scholar 

  26. Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res. 2002;62:13–7.

    PubMed  CAS  Google Scholar 

  27. Grabsch H, Takeno S, Parsons WJ, et al. Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer-association with tumour cell proliferation. J Pathol. 2003;200:16–22.

    Article  PubMed  CAS  Google Scholar 

  28. Tanaka K, Mohri Y, Ohi M, et al. Mitotic checkpoint genes, hsMAD2 and BubR1, in oesophageal squamous cancer cells and their association with 5-fluorouracil and cisplatin-based radiochemotherapy. Clin Oncol (R Coll Radiol). 2008;20(8):639–46.

    Article  CAS  Google Scholar 

  29. Sudo T, Nitta M, Saya H, Ueno NT. Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res. 2004;64(7):2502–8.

    Article  PubMed  CAS  Google Scholar 

  30. Lee EA, Keutmann MK, Dowling ML, Harris E, Chan G, Kao GD. Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells. Mol Cancer Ther. 2004;3(6):661–9.

    PubMed  CAS  Google Scholar 

  31. Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. 2004;117:5721–9.

    Article  PubMed  CAS  Google Scholar 

  32. Hernández F, Avila J. Tauopathies. Cell Mol Life Sci. 2007;64(17):2219–33.

    Article  PubMed  Google Scholar 

  33. Feinstein SC, Wilson L. Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochim Biophys Acta. 2005;1739(2–3):268–79.

    PubMed  CAS  Google Scholar 

  34. Sangrajrang S, Denoulet P, Millot G, et al. Estramustine resistance correlates with tau over-expressıon in human prostatic carcınoma cells. Int J Cancer. 1998;77:626–31.

    Article  PubMed  CAS  Google Scholar 

  35. Mimori K, Sadanaga N, Yoshikawa Y, et al. Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment. Br J Cancer. 2006;94(12):1894–7.

    Article  PubMed  CAS  Google Scholar 

  36. Jimeno A, Hallur G, Chan A, et al. Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer. Mol Cancer Ther. 2007;6:1509–16.

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege Universtiy, Bornova, 35100, Izmir, Turkey

    Yalcin Cirak, Burcu Cakar & Ruchan Uslu

  2. Department of Pathology, School of Medicine, Ege University, Bornova, 35100, Izmir, Turkey

    Banu Sarsik & Sait Sen

  3. Department of Urology, School of Medicine, Ege University, Bornova, 35100, Izmir, Turkey

    Adnan Simsir

Authors
  1. Yalcin Cirak
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  2. Banu Sarsik
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  3. Burcu Cakar
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  4. Sait Sen
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Correspondence to Yalcin Cirak.

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Cirak, Y., Sarsik, B., Cakar, B. et al. Predictive and prognostic values of Tau and BubR1 protein in prostate cancer and their relationship to the Gleason score. Med Oncol 30, 526 (2013). https://doi.org/10.1007/s12032-013-0526-7

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  • DOI: https://doi.org/10.1007/s12032-013-0526-7

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