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Topoisomerase 2 alpha: a real predictor of anthracycline efficacy?

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  • Advances in Translational Oncology
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Abstract

Anthracyclines are frequently used in the adjuvant setting for breast cancer treatment since it is considered that anthracycline-based chemotherapy treatment benefits breast cancer patients. Nonetheless, these drugs are associated with severe side effects and predictive factors, for sensitivity to anthracyclines, are warranted in clinical practice. Topoisomerase 2 alpha (TOP2A) is considered to be the molecular target of these drugs. The potential predictive value of TOP2A amplification and overexpression has been extensively studied in breast cancer patients treated with anthracyclines. However, results are not conclusive. In this paper, we review some of the published studies addressing the predictive value of TOP2A as well as the cellular functions of this enzyme and its status in breast cancer tissue.

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References

  1. Tewey KM, Rowe TC, Yang L et al (1984) Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466–468

    Article  PubMed  CAS  Google Scholar 

  2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  Google Scholar 

  3. Järvinen TA, Kononen J, Pelto-Huikko M, Isola J (1996) Expression of topoisomerase IIalpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer. Am J Pathol 148:2073–2082

    PubMed  Google Scholar 

  4. Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430–440

    Article  PubMed  CAS  Google Scholar 

  5. Osheroff N, Zechiedrich EL, Gale KC (1991) Catalytic function of DNA topoisomerase II. BioEssays 13:269–275

    Article  PubMed  CAS  Google Scholar 

  6. Earnshaw WC, Halligan B, Cooke CA et al (1985) Topoisomerase II is a structural component of mitotic chromosome scaffolds. J Cell Biol 100:1706–1715

    Article  PubMed  CAS  Google Scholar 

  7. Uemura T, Ohkura H, Adachi Y et al (1987) DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50:917–925

    Article  CAS  Google Scholar 

  8. Brown PO, Cozzarelli NR (1979) A sign inversion mechanism for enzymatic supercoiling of DNA. Science 206:1081–1083

    Article  PubMed  CAS  Google Scholar 

  9. Liu LF, Liu CC, Alberts BM (1980) Type II DNA topoisomerases: enzymes that can unknot a topologically knotted DNA molecule via a reversible double-strand break. Cell 19:697–707

    Article  PubMed  CAS  Google Scholar 

  10. Drake FH, Hofmann GA, Bartus HF et al (1989). Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. Biochemistry 28:8154–8160

    Article  PubMed  CAS  Google Scholar 

  11. Goswami PC, Sheren J, Albee LD et al (2000) Cell cycle in coupled variation topoisomerase IIalpha mRNA is regulated by the 30-untranslated region. Possible role of redoxsensitive protein binding in mRNA accumulation. J Biol Chem 275:38384–38392

    Article  PubMed  CAS  Google Scholar 

  12. Christensen MO, Larsen MK, Barthelmes HU et al (2002) Dynamics of human DNA topoisomerases IIα and II β in living cells. J Cell Biol 157:31–44

    Article  PubMed  CAS  Google Scholar 

  13. Sandri MI, Hochhauser D, Ayton P et al (1996) Differential expression of the topoisomerase IIα and β genes in human breast cancer. Br J Cancer 73:1518–1524

    Article  PubMed  CAS  Google Scholar 

  14. Isaacs RJ, Harris AL, Hickson ID (1996) Regulation of the human topoisomerase IIalpha gene promoter in confluence-arrested cells. J Biol Chem 271:16741–16747

    Article  PubMed  CAS  Google Scholar 

  15. Goswami PC, Roti Roti JL, Hunt CR (1996) The cell cycle-coupled expression of topoisomerase IIalpha during S phase is regulated M. by mRNA stability and is disrupted by heat shock or ionizing radiation. Mol Cell Biol 16:1500–1508

    PubMed  CAS  Google Scholar 

  16. Wells NJ, Hickson ID (1995) Human topoisomerase II alpha is phosphorylated in a cell-cycle phase-dependent manner by a proline-directed kinase. Eur J Biochem 231:491–497

    Article  PubMed  CAS  Google Scholar 

  17. Carpenter AJ, Porter AC (2004) Construction, characterization, and complementation of a conditional-lethal DNA topoisomerase IIalpha mutant human cell line. Mol Biol Cell 15:5700–5711

    Article  PubMed  CAS  Google Scholar 

  18. Errington F, Willmore E, Tilby MJ et al (1999) Murine transgenic cells lacking DNA topoisomerase IIbeta are resistant to acridines and mitoxantrone: analysis of cytotoxicity and cleavable complex formation. Mol Pharmacol 56:1309–1316

    PubMed  CAS  Google Scholar 

  19. Turley H, Comley M, Houlbrook S et al (1997) The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues. Br J Cancer 75:1340–1346

    Article  PubMed  CAS  Google Scholar 

  20. McPherson JP, Goldenberg GJ (1998) Induction of apoptosis by deregulated expression of DNA topoisomerase II alpha. Cancer Res 58:4519–4524

    PubMed  CAS  Google Scholar 

  21. Felix CA (1998) Secondary leukemias induced by topoisomerase targeted drugs. Biochim BioPhys Acta 1400:233–255

    PubMed  CAS  Google Scholar 

  22. Wong N, Yeo W, Wong WL et al (2009) TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. Int J Cancer 124:644–652

    Article  PubMed  CAS  Google Scholar 

  23. Shvero J, Koren R, Shvili I et al (2008) Expression of human DNA Topoisomerase II-alpha in squamous cell carcinoma of the larynx and its correlation with clinicopathologic variables. Am J Clin Pathol 130:934–939

    Article  PubMed  Google Scholar 

  24. Bredel M, Pollack IF, Hamilton RL et al (2002) DNA topoisomerase II alpha predicts progression free and overall survival in pediatric malignant non-brainstem gliomas. In J Cancer 99:817–820

    CAS  Google Scholar 

  25. Nakopoulou L, Lazaris AC, Kavantzas N (2000) DNA topoisomerase II alpha immunoreactivity as a marker of aggressiveness in invasive breast cancer. Pathobiology 68:137–143

    Article  PubMed  CAS  Google Scholar 

  26. Petit T, Wilt M, Velten M et al (2004) Comparative value of tumor grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 40:2005–2211

    Article  Google Scholar 

  27. Romero A, Martín M, Cheang MC et al (2011) Assessment of Topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization. Am J Pathol 178:1453–1460

    Article  PubMed  Google Scholar 

  28. Parker JS, Mullins M, Cheang MC et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167

    Article  PubMed  Google Scholar 

  29. Depowski PL, Rosenthal SI, Brien TP et al (2000) Topoisomerase IIalpha expression in breast cancer: correlation with outcome variables. Mod Pathol 13:542–547

    Article  PubMed  CAS  Google Scholar 

  30. Brase JC, Schmidt M, Fischbach T et al (2010) ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16:2391–2401

    Article  PubMed  CAS  Google Scholar 

  31. Rody A, Karn T, Ruckhäberle E et al (2009) Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat 113:457–466

    Article  PubMed  CAS  Google Scholar 

  32. DeAtley SM, Aksenov MY, Aksenova MV et al (1999) Antioxidants protect against reactive oxygen species associated with doxorubicine-treated cardiomyocytes. Cancer Lett 136:41–46

    Article  PubMed  CAS  Google Scholar 

  33. Sarvazyan N (1996) Visualization of doxorubicin-induced oxidative stress in isolated cardiac myocytes. Am J Physiol 271:H2079–H2085

    PubMed  CAS  Google Scholar 

  34. Ravid A, Rocker D, Machlenkin A et al (1999) 1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. Cancer Res 59:862–867

    PubMed  CAS  Google Scholar 

  35. Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229

    Article  PubMed  CAS  Google Scholar 

  36. Ross WE, Glaubiger DL, Kohn KW (1978) Protein-associated DNA breaks in cells treated with adriamycin or ellipticine. Biochim Biophys Acta 519:23–30

    PubMed  CAS  Google Scholar 

  37. Zwelling LA, Michaels S, Erickson LC et al (1981) Protein-associated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic acid intercalating agents 4′-(9-acridinylamino) methanesulfon-m-anisidide and adriamycin. Biochemistry 20:6553–6563

    Article  PubMed  CAS  Google Scholar 

  38. Tewey KM, Chen GL, Nelson EM, Liu LF (1984) Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259:9182–9187

    PubMed  CAS  Google Scholar 

  39. Davies SM, Robson CN, Davies SL, Hickson ID (1988) Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins. J Biol Chem 263:17724–17729

    PubMed  CAS  Google Scholar 

  40. Gudkov AV, Zelnick CR, Kazarov AR et al (1993) Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. Proc Natl Acad Sci U S A 90:3231–3235

    Article  PubMed  CAS  Google Scholar 

  41. Mo YY, Ameiss KA, Beck WT (1998) Overexpression of human DNA topoisomerase II alpha by fusion to enhanced green fluorescent protein. Biotechniques 25:1052–1057

    PubMed  CAS  Google Scholar 

  42. Thor AD, Berry DA, Budman DR et al (1998) ErbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90:1346–1360

    Article  PubMed  CAS  Google Scholar 

  43. Paik S, Bryant J, Park C et al (1998) ErbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer J Natl Cancer Inst 90:1361–1370

    Article  PubMed  CAS  Google Scholar 

  44. Paik S, Bryant J, Tan-Chiu E et al (2000) ERBB2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92:1991–1998

    Article  PubMed  CAS  Google Scholar 

  45. Pritchard KI, Shepherd LE, O’Malley FP et al (2006) ERBB2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354: 2103–2111

    Article  PubMed  CAS  Google Scholar 

  46. Gennari A, Sormani MP, Pronzato P et al (2008) ERBB2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20

    Article  PubMed  CAS  Google Scholar 

  47. De Laurentiis M, Arpino G, Massarelli E et al (2005) A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 11:4741–4748

    Article  PubMed  Google Scholar 

  48. Bartlett JM, Munro A, Cameron DA et al (2008) Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 26:5027–5035

    Article  PubMed  CAS  Google Scholar 

  49. Olsen KE, Knudsen H, Rasmussen BB et al; Danish Breast Cancer Co-operative Group (2004) Amplification of ERBB2 and TOP2A and deletion of TOP2A genes in breast cancer investigated by new FISH probes. Acta Oncol 43:35–42

    Article  PubMed  CAS  Google Scholar 

  50. Järvinen TA, Tanner M, Bärlund M et al (1999) Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 26:142–150

    Article  PubMed  Google Scholar 

  51. Press MF, Sauter G, Buyse M et al (2011) Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 29:859–867

    Article  PubMed  CAS  Google Scholar 

  52. Scandinavian Breast Group Trial 9401, Tanner M, Isola J, Wiklund T et al (2006) Topoisomerase II alpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 24:2428–2436

    Article  PubMed  CAS  Google Scholar 

  53. Arriola E, Rodriguez-Pinilla SM, Lambros MB et al (2007) Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat 106:181–189

    Article  PubMed  CAS  Google Scholar 

  54. Knoop AS, Knudsen H, Balslev E et al; Danish Breast Cancer Cooperative Group (2005) Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil. J Clin Oncol 23:7483–7490

    Article  PubMed  CAS  Google Scholar 

  55. O’Malley FP, Chia S, Tu D et al (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:644–650

    Article  PubMed  Google Scholar 

  56. Harris LN, Broadwater G, Abu-Khalaf M et al (2009) Topoisomerase II {alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in ERBB2-amplified early breast cancer: results of CALGB 8541/150013. J Clin Oncol 27:3430–3436

    Article  PubMed  CAS  Google Scholar 

  57. Hannemann J, Kristel P, van Tinteren H et al (2006) Molecular subtypes of breast cancer and amplification of topoisomerase IIa: predictive role in dose intensive adjuvant chemotherapy. Br J Cancer 95:1334–1341

    Article  PubMed  CAS  Google Scholar 

  58. Bartlett JM, Munro AF, Dunn JA et al (2010) Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol 11:266–274

    Article  PubMed  CAS  Google Scholar 

  59. Di Leo A, Isola J, Piette F et al (2008) A metaanalysis of phase III trials evaluating the predictive value of HER2 and topoisomerase II alpha in early breast cancer patients treated with CMF or anthracyclines-based adjuvant therapy. Presented at the 31st Annual San Antonio Breast Cancer Symposium, 10–14 December, 2008, San Antonio, TX, abstr 705

  60. Di Leo A, Desmedt C, Bartlett JMS et al (2011) HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 12:1134–1142

    Article  PubMed  Google Scholar 

  61. Järvinen TA, Holli K, Kuukasjärvi T, Isola JJ (1998). Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer. Br J Cancer 77:2267–2273

    Article  PubMed  Google Scholar 

  62. Petit T, Wilt M, Velten M et al (2004) Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Eur J Cancer 40:205–211

    Article  PubMed  CAS  Google Scholar 

  63. Desmedt C, Di Leo A, de Azambuja E et al (2011) Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol 29:1578–1586

    Article  PubMed  CAS  Google Scholar 

  64. G Estevez L, Fortes JL, Adrover E et al (2009) Doxorubicin and cyclophosphamide followed by weekly docetaxel as neoadjuvant treatment of early breast cancer: analysis of biological markers in a GEICAM phase II study. Clin Transl Oncol 11:54–59

    Article  CAS  Google Scholar 

  65. Durbecq V, Paesmans M, Cardoso F et al (2004) Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 3:1207–1214

    PubMed  CAS  Google Scholar 

  66. Brase JC, Schmidt M, Fischbach T et al (2010) ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16:2391–2401

    Article  PubMed  CAS  Google Scholar 

  67. O’Malley FP, Chia S, Tu D et al (2011) Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial. Breast Cancer Res Treat 128:401–409

    Article  PubMed  Google Scholar 

  68. Fritz P, Cabrera CM, Dippon J et al (2005) cerbB2 and topoisomerase IIalpha protein expression independently predict poor survival in primary human breast cancer: a retrospective study. Breast Cancer Res 7:R374–384

    Article  PubMed  CAS  Google Scholar 

  69. Sparano JA, Goldstein LJ, Childs BH et al (2009) Relationship between topoisomerase 2A RNA expression and recurrence after adjuvant chemotherapy for breast cancer. Clin Cancer Res 15: 7693–7700

    Article  PubMed  CAS  Google Scholar 

  70. Martin M, Romero A, Cheang MC et al (2011) Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat 128:127–136

    Article  PubMed  CAS  Google Scholar 

  71. Prat A, Parker JS, Karginova O et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68

    Article  PubMed  Google Scholar 

  72. Carey LA, Perou CM, Livasy CA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295:2492–2502

    Article  PubMed  CAS  Google Scholar 

  73. Rouzier R, Perou CM, Symmans WF et al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685

    Article  PubMed  CAS  Google Scholar 

  74. Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology Department, Hospital Clínico San Carlos, C/ Prof Martín Lago, s/n, ES-28040, Madrid, Spain

    Atocha Romero, Trinidad Caldés & Eduardo Díaz-Rubio

  2. Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Miguel Martín

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  1. Atocha Romero
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  2. Trinidad Caldés
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  3. Eduardo Díaz-Rubio
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  4. Miguel Martín
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Correspondence to Trinidad Caldés.

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Romero, A., Caldés, T., Díaz-Rubio, E. et al. Topoisomerase 2 alpha: a real predictor of anthracycline efficacy?. Clin Transl Oncol 14, 163–168 (2012). https://doi.org/10.1007/s12094-012-0779-1

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