Breast Cancer Research and Treatment

, Volume 115, Issue 3, pp 651–659 | Cite as

Cyclin E deregulation is an early event in the development of breast cancer

  • Alexandra Shaye
  • Aysegul Sahin
  • Qiang Hao
  • Kelly Hunt
  • Khandan Keyomarsi
  • Isabelle BedrosianEmail author


Cyclin E has been shown to be overexpressed in some human breast cancers, however, data to support deregulation of cyclin E as an early event in human mammary tumor development is lacking. We analyzed surgical specimens from 183 patients with breast carcinomas and evaluated cyclin E expression in areas of invasive carcinoma, adjacent carcinoma in situ (CIS), and non-neoplastic breast parenchyma. Overexpression of cyclin E was seen in one-third of invasive carcinoma samples, one-third of the CIS component and nearly half of the non-neoplastic breast epithelial cells adjacent to carcinoma (44% vs. 33%, P ≤ 0.05). Nuclear labeling for cyclin E was highly concordant between areas of in invasive carcinoma, CIS and non-neoplastic breast epithelial cells from the same patient (P < 0.0001). Localization of cyclin E to the cytoplasm was seen in a small proportion of tumor samples. Our findings suggest that cyclin E deregulation is an early event in the progression from histologically benign mammary epithelial cells to invasive carcinoma and occurs through both overexpression and altered cellular localization.


Cyclin E Premalignant breast disease Breast cancer Cytoplasmic localization 



The authors wish to thank Robyn Kuhn and Roland L. Bassett Jr. for their assistance with the statistical analysis. Supported by Texas Federation of Business and Professional Women and National Institutes of Health grant CA116199 (SPORE in Breast Cancer).


  1. 1.
    Sherr CJ (1996) Cancer cell cycles. Science 274(5293):1672–1677. doi: 10.1126/science.274.5293.1672 PubMedCrossRefGoogle Scholar
  2. 2.
    Koff A, Giordano A, Desia D, Yamashita K, Harper J, Elledge S, Nishomoto T, Morgan D, Franza R, Roberts J (1992) Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257:1689–1694. doi: 10.1126/science.1388288 PubMedCrossRefGoogle Scholar
  3. 3.
    Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN (2005) Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. Clin Cancer Res 11(4):1447–1453. doi: 10.1158/1078-0432.CCR-04-1730 PubMedCrossRefGoogle Scholar
  4. 4.
    Tissier F, Louvel A, Grabar S, Hagnere AM, Bertherat J, Vacher-Lavenu MC, Dousset B, Chapuis Y, Bertagna X, Gicquel C (2004) Cyclin E correlates with malignancy and adverse prognosis in adrenocortical tumors. Eur J Endocrinol 150(6):809–817. doi: 10.1530/eje.0.1500809 PubMedCrossRefGoogle Scholar
  5. 5.
    Ferreri AJ, Ponzoni M, Pruneri G, Freschi M, Rossi R, Dell’Oro S, Baldini L, Buffa R, Carboni N, Villa E et al (2001) Immunoreactivity for p27(KIP1) and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin’s lymphoma. Int J Cancer 94(4):599–604. doi: 10.1002/ijc.1509 PubMedCrossRefGoogle Scholar
  6. 6.
    Farley J, Smith LM, Darcy KM, Sobel E, O’Connor D, Henderson B, Morrison LE, Birrer MJ (2003) Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study. Cancer Res 63(6):1235–1241PubMedGoogle Scholar
  7. 7.
    Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, Bedrosian I, Knickerbocker C, Toyofuku W, Lowe M et al (2002) Cyclin E and survival in patients with breast cancer. N Engl J Med 347(20):1566–1575. doi: 10.1056/NEJMoa021153 PubMedCrossRefGoogle Scholar
  8. 8.
    Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM (1997) Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3(2):222–225. doi: 10.1038/nm0297-222 PubMedCrossRefGoogle Scholar
  9. 9.
    Fukuse T, Hirata T, Naiki H, Hitomi S, Wada H (2000) Prognostic significance of cyclin E overexpression in resected non- small cell lung cancer. Cancer Res 60(2):242–244PubMedGoogle Scholar
  10. 10.
    Jang SJ, Park YW, Park MH, Lee JD, Lee YY, Jung TJ, Kim IS, Choi IY, Ki M, Choi BY et al (1999) Expression of cell-cycle regulators, cyclin E and p21WAF1/CIP1, potential prognostic markers for gastric cancer. Eur J Surg Oncol 25(2):157–163. doi: 10.1053/ejso.1998.0619 PubMedCrossRefGoogle Scholar
  11. 11.
    Mishina T, Dosaka-Akita H, Hommura F, Nishi M, Kojima T, Ogura S, Shimizu M, Katoh H, Kawakami Y (2000) Cyclin E expression, a potential prognostic marker for non-small cell lung cancers. Clin Cancer Res 6(1):11–16PubMedGoogle Scholar
  12. 12.
    Rosen DG, Yang G, Deavers MT, Malpica A, Kavanagh JJ, Mills GB, Liu J (2006) Cyclin E expression is correlated with tumor progression and predicts a poor prognosis in patients with ovarian carcinoma. Cancer 106(9):1925–1932. doi: 10.1002/cncr.21767 PubMedCrossRefGoogle Scholar
  13. 13.
    Keyomarsi K, Pardee A (1993) Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 90:1112–1116. doi: 10.1073/pnas.90.3.1112 PubMedCrossRefGoogle Scholar
  14. 14.
    Porter D, Zhang N, Danes C, McGrehan M, Harwell R, Farouk S, Keyomarsi K (2001) Tumor specific proteolytic processing of cyclin E generates hyper-active lower molecular weight forms. Mol Cell Biol 21:6254–6269. doi: 10.1128/MCB.21.18.6254-6269.2001 PubMedCrossRefGoogle Scholar
  15. 15.
    Spruck CH, Won KA, Reed SI (1999) Deregulated cyclin E induces chromosome instability. Nature 401(6750):297–300. doi: 10.1038/45836 PubMedCrossRefGoogle Scholar
  16. 16.
    Bortner DM, Rosenberg MP (1997) Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 17(1):453–459PubMedGoogle Scholar
  17. 17.
    Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, Tucker SL, Chang S, Keyomarsi K (2004) Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res 64(9):3198–3208. doi: 10.1158/0008-5472.CAN-03-3672 PubMedCrossRefGoogle Scholar
  18. 18.
    Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434(7035):864–870. doi: 10.1038/nature03482 PubMedCrossRefGoogle Scholar
  19. 19.
    Tort F, Bartkova J, Sehested M, Orntoft T, Lukas J, Bartek J (2006) Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis. Cancer Res 66(21):10258–10263. doi: 10.1158/0008-5472.CAN-06-2178 PubMedCrossRefGoogle Scholar
  20. 20.
    Jirstrom K, Ringberg A, Ferno M, Anagnostaki L, Landberg G (2003) Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence. Br J Cancer 89(10):1920–1926. doi: 10.1038/sj.bjc.6601398 PubMedCrossRefGoogle Scholar
  21. 21.
    Scott KA, Walker RA (1997) Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer. Br J Cancer 76(10):1288–1292PubMedGoogle Scholar
  22. 22.
    Donnellan R, Kleinschmidt I, Chetty R (2001) Cyclin E immunoexpression in breast ductal carcinoma: pathologic correlations and prognostic implications. Hum Pathol 32(1):89–94. doi: 10.1053/hupa.2001.21141 PubMedCrossRefGoogle Scholar
  23. 23.
    Peters MG, Vidal Mdel C, Gimenez L, Mauro L, Armanasco E, Cresta C, de Bal Kier Joffe E, Puricelli L (2004) Prognostic value of cell cycle regulator molecules in surgically resected stage I and II breast cancer. Oncol Rep 12(5):1143–1150PubMedGoogle Scholar
  24. 24.
    Reed W, Sandstad B, Holm R, Nesland JM (2003) The prognostic impact of hormone receptors and c-erbB-2 in pregnancy-associated breast cancer and their correlation with BRCA1 and cell cycle modulators. Int J Surg Pathol 11(2):65–74. doi: 10.1177/106689690301100201 PubMedCrossRefGoogle Scholar
  25. 25.
    Han S, Park K, Bae BN, Kim KH, Kim HJ, Kim YD, Kim HY (2003) 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 83(4):241–247. doi: 10.1002/jso.10268 PubMedCrossRefGoogle Scholar
  26. 26.
    Potemski P, Kusinska R, Watala C, Pluciennik E, Bednarek AK, Kordek R (2005) Prognostic relevance of basal cytokeratin expression in operable breast cancer. Oncology 69(6):478–485. doi: 10.1159/000090986 PubMedCrossRefGoogle Scholar
  27. 27.
    Kim HK, Park IA, Heo DS, Noh DY, Choe KJ, Bang YJ, Kim NK (2001) Cyclin E overexpression as an independent risk factor of visceral relapse in breast cancer. Eur J Surg Oncol 27(5):464–471. doi: 10.1053/ejso.2001.1137 PubMedCrossRefGoogle Scholar
  28. 28.
    Chappuis PO, Donato E, Goffin JR, Wong N, Begin LR, Kapusta LR, Brunet JS, Porter P, Foulkes WD (2005) Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment. Ann Oncol 16(5):735–742. doi: 10.1093/annonc/mdi149 PubMedCrossRefGoogle Scholar
  29. 29.
    Rao S, Lowe M, Herliczek T, Keyomarsi K (1998) Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene 17:2393–2402. doi: 10.1038/sj.onc.1202322 PubMedCrossRefGoogle Scholar
  30. 30.
    Nielsen NH, Arnerlov C, Emdin SO, Landberg G (1996) Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status. Br J Cancer 74(6):874–880PubMedGoogle Scholar
  31. 31.
    Potemski P, Kusinska R, Watala C, Pluciennik E, Bednarek AK, Kordek R (2006) Cyclin E expression in breast cancer correlates with negative steroid receptor status, HER2 expression, tumor grade and proliferation. J Exp Clin Cancer Res 25(1):59–64PubMedGoogle Scholar
  32. 32.
    Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M (1995) Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 15(5):2612–2624PubMedGoogle Scholar
  33. 33.
    Fang F, Orend G, Watanabe N, Hunter T, Ruoslahti E (1996) Dependence of cyclin E-cdk2 kinase activity on cell anchorage. Science 271:499–502. doi: 10.1126/science.271.5248.499 PubMedCrossRefGoogle Scholar
  34. 34.
    Span PN, Tjan-Heijnen VC, Manders P, Beex LV, Sweep CG (2003) Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer. Oncogene 22(31):4898–4904. doi: 10.1038/sj.onc.1206818 PubMedCrossRefGoogle Scholar
  35. 35.
    Akli S, Van Pelt CS, Bui T, Multani AS, Chang S, Johnson D, Tucker S, Keyomarsi K (2007) Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway. Cancer Res 67(15):7212–7222. doi: 10.1158/0008-5472.CAN-07-0599 PubMedCrossRefGoogle Scholar
  36. 36.
    Geng Y, Lee YM, Welcker M, Swanger J, Zagozdzon A, Winer JD, Roberts JM, Kaldis P, Clurman BE, Sicinski P (2007) Kinase-independent function of cyclin E. Mol Cell 25(1):127–139. doi: 10.1016/j.molcel.2006.11.029 PubMedCrossRefGoogle Scholar
  37. 37.
    Jackman M, Kubota Y, den Elzen N, Hagting A, Pines J (2002) Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm. Mol Biol Cell 13(3):1030–1045. doi: 10.1091/mbc.01-07-0361 PubMedCrossRefGoogle Scholar
  38. 38.
    Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE et al (2000) Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103(1):127–140. doi: 10.1016/S0092-8674(00)00093-3 PubMedCrossRefGoogle Scholar
  39. 39.
    Moore JD, Kornbluth S, Hunt T (2002) Identification of the nuclear localization signal in Xenopus cyclin E and analysis of its role in replication and mitosis. Mol Biol Cell 13(12):4388–4400. doi: 10.1091/mbc.E02-07-0449 PubMedCrossRefGoogle Scholar
  40. 40.
    Furuno N, den Elzen N, Pines J (1999) Human cyclin A is required for mitosis until mid prophase. J Cell Biol 147(2):295–306. doi: 10.1083/jcb.147.2.295 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Alexandra Shaye
    • 1
  • Aysegul Sahin
    • 1
  • Qiang Hao
    • 2
  • Kelly Hunt
    • 2
    • 3
  • Khandan Keyomarsi
    • 2
    • 3
  • Isabelle Bedrosian
    • 2
    Email author
  1. 1.Department of PathologyUniversity of Texas, M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Surgical OncologyUniversity of Texas, M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of Experimental Radiation OncologyUniversity of Texas, M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations