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Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogen receptor-positive and human epidermal growth factor type-2-negative breast cancer

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Abstract

Background

Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer.

Materials and methods

Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI).

Results

Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p = 0.036), and LVI (p = 0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p < 0.0001). A statistically significant difference was observed between the Ki-67 LI and nuclear grade (p = 0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p = 0.003).

Conclusions

Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.

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References

  1. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784–92.

    Article  CAS  PubMed  Google Scholar 

  2. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ, 10th St Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007;18:1133–44.

    Article  CAS  PubMed  Google Scholar 

  3. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ, Panel members. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20:1319–29.

    Article  CAS  PubMed  Google Scholar 

  4. Piccart MJ, Di Leo A, Hamilton A. HER2. a ‘predictive factor’ ready to use in the daily management of breast cancer patients? Eur J Cancer. 2000;36:1755–61.

    Article  CAS  PubMed  Google Scholar 

  5. Yamauchi H, Stearns V, Hayes DF. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol. 2001;19:2334–56.

    CAS  PubMed  Google Scholar 

  6. Järvinen TA, Tanner M, Rantanen V, Bärlund M, Borg A, Grénman S, et al. Amplification and deletion of topoisomerase IIalpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol. 2000;156:839–47.

    Article  PubMed  Google Scholar 

  7. Tan KB, Dorman TE, Falls KM, Chung TDY, Mirabelli CK, Crooke ST, et al. Topoisomerase II alpha and topoisomerase II beta differentially spliced forms of topoisomerase II alpha mRNA. Nucleic Acids Res. 1993;21:3719–23.

    Article  Google Scholar 

  8. Withoff S, De Jong S, De Vries EGE, Mulder NH. Human DNA topoisomerase II: biochemistry and role in chemotherapy resistance. Anticancer Res. 1996;16:1867–80.

    CAS  PubMed  Google Scholar 

  9. Chung DU, Drake SH, Tan KB, Per SR, Crooke ST, Mirabelli CK. Characterization and immunological identification of cDNA clones encoding to human topoisomerase isozymes. Proc Natl Acad Sci USA. 1989;86:9431–5.

    Article  CAS  PubMed  Google Scholar 

  10. Roca J, Wang JC. DNA transport by a type II DNA topoisomerase: evidence in favor of a two-gate mechanism. Cell. 1994;77:609–16.

    Article  CAS  PubMed  Google Scholar 

  11. Osheroff N. Biochemical basis for the interactions of type I and type II topoisomerase with DNA. Pharmacol Ther. 1989;41:223–41.

    Article  CAS  PubMed  Google Scholar 

  12. Gerdes J, Schwab U, Lemke H, Stein H. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer. 1983;31:13–20.

    Article  CAS  PubMed  Google Scholar 

  13. Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.

    Article  CAS  PubMed  Google Scholar 

  14. Umemura S, Komaki K, Noguchi S, Shiba E, Toi M, Kimijima I, et al. Prognostic factors for node-negative breast cancers: results of a study program by the Japanese Breast Cancer Society. Breast Cancer. 1998;5:243–9.

    Article  PubMed  Google Scholar 

  15. Railo M, Nordling S, von Boguslawsky K, Leivonen M, Kyllönen L, von Smitten K. Prognostic value of Ki-67 immunolabelling in primary operable breast cancer. Br J Cancer. 1993;68:579–83.

    Article  CAS  PubMed  Google Scholar 

  16. Nishimura R, Nagao K, Miyayama H, Matsuda M, Baba K, Matsuoka Y, et al. An evaluation of predictive factors involved in clinical or pathological response to primary chemotherapy in advanced breast cancer. Breast Cancer. 2002;9:145–52.

    Article  PubMed  Google Scholar 

  17. Giuseppe Viale, Anita Giobbie-Hurder, Regan MM, Coates AS, Mastropasqua MG, Dell’Orto P, et al. Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol. 2008;26:5569–75.

    Article  Google Scholar 

  18. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, A’Hern R, et al. Prognostic value of Ki-67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99:167–70.

    Article  CAS  PubMed  Google Scholar 

  19. Nishimura R, Osako T, Okumura Y, Hayashi M, Arima N. Clinical significance of Ki-67 in neoadjuvant chemotherapy for primary breast cancer as a predictor for chemosensitivity and for prognosis. Breast Cancer. 2010;17:269–75.

    Article  PubMed  Google Scholar 

  20. Kurosumi M, Suemasu K, Tabei T, Inoue K, Matsumoto H, Sugamata N, et al. Relationship between existence of lymphatic invasion in peritumoral breast tissue and presence of axillary lymph node metastasis in invasive ductal carcinoma of the breast. Oncol Rep. 2001;8:1051–5.

    CAS  PubMed  Google Scholar 

  21. Di Leo A, Larsimont D, Gancberg D, Jarvinen T, Beauduin M, Vindevoghel A, et al. HER-2 and topo-isomerase Ha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol. 2001;12:1081–9.

    Article  CAS  PubMed  Google Scholar 

  22. Cardoso F, Durbecq V, Larsimont D, Paensmans M, Leroy J, Rouas G et al. Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-α gene amplification and protein overexpression in locally advanced/metastatic breast cancer. Int J Oncol. 2004;24:201–9.

    Google Scholar 

  23. Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ, et al. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene. 1997;15:537–47.

    Article  CAS  PubMed  Google Scholar 

  24. Orlando L, Del Curto B, Gandini S, Ghisini R, Pietri E, Torrisi R, et al. Topoisomerase IIα gene status and prediction of pathological complete remission after anthracycline-based neoadjuvant chemotherapy in endocrine non-responsive Her2/neu-positive breast cancer. Breast. 2008;17:506–11.

    Article  PubMed  Google Scholar 

  25. O’Malley FP, Chia S, Tu D, Shepherd L, Levine M, Huntsman D, et al. Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer. Breast Cancer Res Treat. 2006;100:S18.

    Google Scholar 

  26. Martin-Richard M, Muñoz J, Albanell L, Colomo M, Bellet MJ, Rey J, et al. Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy. Oncology. 2004;66:388–94.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu L, Li YF, Chen WG, He JR, Peng CH, Zhu ZG, et al. HER2 and topoisomerase IIα: possible predictors of response to neoadjuvant chemotherapy for breast cancer patients. Chin Med J. 2008;121:1965–8.

    PubMed  Google Scholar 

  28. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.

    CAS  PubMed  Google Scholar 

  29. Rody A, Karn T, Ruckhäberle, Müller V, Gehrmann M, Solbach C et al. Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat. 2009;113:457–66.

  30. Lynch BJ, Guinee DG Jr, Holden JA. Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer. Hum Pathol. 1997;28:1180–8.

    Article  CAS  PubMed  Google Scholar 

  31. Järvinen TA, Kononen J, Pelto-Huikko M, Isola J. Expression of topoisomerase IIalpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer. Am J Pathol. 1996;148:2073–82.

    PubMed  Google Scholar 

  32. Sandri MI, Hochhauser D, Ayton P, Camplejohn RC, Whitehouse R, Turley H, et al. Differential expression of the topoisomerase II alpha and beta genes in human breast cancers. Br J Cancer. 1996;73:1518–24.

    Article  CAS  PubMed  Google Scholar 

  33. Järvinen TA, Holli K, Kuukasjarvi T, Isola JJ. Predictive value of topoisomerase II alpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer. Br J Cancer. 1998;77:2267–73.

    Article  PubMed  Google Scholar 

  34. Gómez HL, Pinto JA, Olivera M, Vidaurre T, Doimi FD, Vigil CE, et al. Topoisomerase IIa as a predictive factor of response to therapy with anthracyclines in locally advanced breast cancer. Breast. 2011;20(1):39–45.

    Article  PubMed  Google Scholar 

  35. Depowski PL, Rosenthal SI, Brien TP, Stylos S, Johnson RL, Ross JS. Topoisomerase IIalpha expression in breast cancer: correlation with outcome variables. Mod Pathol. 2000;13(5):542–7.

    Article  CAS  PubMed  Google Scholar 

  36. Schindlbeck C, Mayr D, Olivier C, Rack B, Engelstaedter V, Jueckstock J, et al. Topoisomerase IIalpha expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer. J Cancer Res Clin Oncol. 2010;136(7):1029–37.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Dean Award (C-002) and the Gunma University Graduate School of Medicine.

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Authors and Affiliations

  1. Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Hideaki Tokiniwa, Jun Horiguchi, Daisuke Takata, Mami Kikuchi, Nana Rokutanda, Rin Nagaoka, Ayako Sato, Hiroki Odawara, Katsunori Tozuka & Izumi Takeyoshi

  2. Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Tetsunari Oyama

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  1. Hideaki Tokiniwa
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Correspondence to Hideaki Tokiniwa.

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Tokiniwa, H., Horiguchi, J., Takata, D. et al. Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogen receptor-positive and human epidermal growth factor type-2-negative breast cancer. Breast Cancer 19, 309–314 (2012). https://doi.org/10.1007/s12282-011-0291-4

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  • DOI: https://doi.org/10.1007/s12282-011-0291-4

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