Tumor Biology

, Volume 34, Issue 6, pp 3423–3430 | Cite as

Prognostic value of cyclin E expression in breast cancer: a meta-analysis

Research Article


Cyclin E is an important regulator of cell cycle progression. Various studies examined the relationship between cyclin E overexpression with the clinical outcome in patients with breast cancer but yielded conflicting results. Electronic databases updated to May 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between cyclin E overexpression and survival of patients with breast cancer. Survival data were aggregated and quantitatively analyzed. We conducted a final analysis of 7,759 patients from 23 eligible studies and evaluated the correlation between cyclin E overexpression and survival in patients with breast cancer. Combined hazard ratios suggested that cyclin E overexpression had an unfavorable impact on overall survival (OS) (hazard ratio (HR) = 1.30, 95 % confidence interval (CI), 1.12–1.49) and breast cancer-specific survival (BCSS) (HR = 1.48, 95 % CI, 1.03–1.93), but not disease-free survival (HR = 1.11; 95 % CI, 0.96–1.27) in patients with breast cancer. Significantly, risks were found among stage I–II breast cancer for (HR = 1.75; 95 % CI, 1.30–2.19). Cyclin E overexpression is associated with poor OS and BCSS in breast cancer.


Cyclin E Breast cancer Prognosis Disease-free survival Meta-analysis 



This work was supported in part by the National Natural Science Foundation of China (81172501).

Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Saurel CA, Patel TA, Perez EA. Changes to adjuvant systemic therapy in breast cancer: a decade in review. Clin Breast Cancer. 2010;10:196–208.PubMedCrossRefGoogle Scholar
  3. 3.
    Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ. Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol. 2005;16:1723–39.PubMedCrossRefGoogle Scholar
  4. 4.
    Hayes DF. Prognostic and predictive factors revisited. Breast. 2008;14:493–9.CrossRefGoogle Scholar
  5. 5.
    Callagy GM, Webber MJ, Pharoah PD, Caldas C. Meta-analysis confirms BCL2 is an independent prognostic marker in breast cancer. BMC Cancer. 2008;8:153.PubMedCrossRefGoogle Scholar
  6. 6.
    Tandis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin. 1998;48:6–29.CrossRefGoogle Scholar
  7. 7.
    Qu Z, Weiss JN, MacLellan WR. Regulation of the mammalian cell cycle: a model of the G1-to-S transition. Am J Physiol Cell Physiol. 2003;284:349–64.CrossRefGoogle Scholar
  8. 8.
    Bortner DM, Rosenberg MP. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol. 1997;17:453–9.PubMedGoogle Scholar
  9. 9.
    Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995;15:2612–24.PubMedGoogle Scholar
  10. 10.
    Ekholm-Reed S, Mendez J, Tedesco D, Zetterberg A, Stillman B, Reed SI. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J Cell Biol. 2004;165:789–800.PubMedCrossRefGoogle Scholar
  11. 11.
    Berglund P, Landberg G. Cyclin E overexpression reduces infiltrative growth in breast cancer. Cell Cycle. 2006;5(6):606–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Altman DG. Systematic reviews of evaluations of prognostic variables. BMJ. 2001;323(7306):224–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Yusuf S, Peto R, Lewis J, et al. Blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–71.PubMedCrossRefGoogle Scholar
  15. 15.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  16. 16.
    Egger M, Smith GD, Schneider M. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.PubMedCrossRefGoogle Scholar
  18. 18.
    Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, et al. Expression of cell cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med. 1997;3(2):222–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Donnellan R, Kleinschmidt I, Chetty R. Cyclin E immunoexpression in breast ductal carcinoma: pathologic correlations and prognostic implications. Hum Pathol. 2001;32(1):89–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim HK, Park IA, Heo DS, Noh DY, Choe KJ, et al. Cyclin E overexpression as an independent risk factor of visceral relapse in breast cancer. Eur J Surg Oncol. 2001;27(5):464–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Bukholm IR, Bukholm G, Nesland JM. Overexpression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas. Int J Cancer. 2001;93(2):283–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, et al. Cyclin E and survival in patients with breast cancer. N Engl J Med. 2002;347(20):1566–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Span PN, Tjan-Heijnen V, Manders P, Beex LV, Sweep CG. Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer. Oncogene. 2003;22(31):4898–904.PubMedCrossRefGoogle Scholar
  24. 24.
    Han S, Park K, Bae BN, Kim KH, Kim HJ, Kim YD, et al. Prognostic implication of cyclin E expression and its relationship with cyclin D1 and p27Kip1 expression on tissue microarrays of node negative breast cancer. J Surg Oncol. 2003;83(4):241–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Rudolph P, Kuhling H, Alm P, Ferno M, Baldetorp B, et al. Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node-negative breast cancer. Int J Cancer. 2003;105(5):674–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Peters MG, Vidal Mdel C, Gimenez L, Mauro L, Armanasco E, et al. Prognostic value of cell cycle regulator molecules in surgically resected stage I and II breast cancer. Oncol Rep. 2004;12(5):1143–50.PubMedGoogle Scholar
  27. 27.
    Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, et al. The prognostic implication of the basal-like (cyclin E high/p27low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 2004;64(3):830–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Lindahl T, Landberg G, Ahlgren J, Nordgren H, Norberg T, et al. Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer. Carcinogenesis. 2004;25(3):375–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Chappuis PO, Donato E, Goffin JR, Wong N, Bégin LR, Kapusta LR, et al. Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment. Ann Oncol. 2005;16(5):735–42.PubMedCrossRefGoogle Scholar
  30. 30.
    Arnes JB, Brunet JS, Stefansson I, Bégin LR, Wong N, Chappuis PO, et al. Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res. 2005;11(11):4003–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Brennan DJ, Jirstrom K, Kronblad A, Millikan RC, Landberg G, Duffy MJ, et al. CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res. 2006;12(21):6421–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Callagy GM, Pharoah PD, Pinder SE, Hsu FD, Nielsen TO, Ragaz J, et al. Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index. Clin Cancer Res. 2006;12(8):2468–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Desmedt C, Ouriaghli FE, Durbecq V, Soree A, Colozza MA, Azambuja E, et al. Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients. Int J Cancer. 2006;119(11):2539–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Sieuwerts AM, Look MP, Meijer-van Gelder ME, Timmermans M, Trapman AM, Garcia RR, et al. Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients. Clin Cancer Res. 2006;12(11 Pt 1):3319–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Porter PL, Barlow WE, Yeh IT, Lin MG, Yuan XP, Donato E, et al. p27(Kip1) and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy. J Natl Cancer Inst. 2006;98(23):1723–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Potemski P, Pluciennik E, Bednarek AK, Kusinska R, Jesionek-Kupnicka D, Pasz-Walczak G, et al. Cyclin E expression in operable breast cancer quantified using real-time RT-PCR: a comparative study with immunostaining. Jpn J Clin Oncol. 2006;36(3):142–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Somlo G, Chu P, Frankel P, Ye W, Groshen S, Doroshow JH, et al. Molecular profiling including epidermal growth factor receptor and p21 expression in high-risk breast cancer patients as indicators of outcome. Ann Oncol. 2008;19(11):1853–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Potemski P, Kusińska R, Pasz-Walczak G, Piekarski JH, Watała C, Płuciennik E, et al. Prognostic relevance of cyclin E expression in operable breast cancer. Med Sci Monit. 2009;15(2):MT34–40.PubMedGoogle Scholar
  39. 39.
    Sgambato A, Camerini A, Collecchi P, Graziani C, Bevilacqua G, Capodanno A, et al. Cyclin E correlates with manganese superoxide dismutase expression and predicts survival in early breast cancer patients receiving adjuvant epirubicin-based chemotherapy. Cancer Sci. 2009;100(6):1026–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Lemée F, Bergoglio V, Fernandez-Vidal A, Machado-Silva A, Pillaire MJ, Bieth A, et al. DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability. Proc Natl Acad Sci U S A. 2010;107(30):13390–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Koff A, Giordano A, Desai D, Yamashita K, Harper JW, et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992;257:1689–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Sauer K, Lehner CF. The role of cyclin E in the regulation of entry into S phase. Prog Cell Cycle Res. 1995;1:125–39.PubMedCrossRefGoogle Scholar
  43. 43.
    Malumbres M, Barbacid M. To cycle or not cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1:222–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev. 1996;10:1979–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature. 2001;413:311–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Wingate H, Puskas A, Duong M, Bui T, Richardson D, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle. 2009;8:1062–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Wang L, Shao ZM. Cyclin E expression and prognosis in breast cancer patients: a meta-analysis of published studies. Cancer Invest. 2006;24:581–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Begg CB, Berlin JA. Publication bias: a problem in interpreting medical data. J R Stat Soc A. 1988;151:419–63.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.State Key Laboratory of Reproductive Medicine, Department of Breast SurgeryNanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical UniversityNanjingChina

Personalised recommendations