Human Pathology
Volume 39, Issue 10 , Pages 1431-1437 , October 2008

The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype

  • David Voduc, MD, FRCPC

      Affiliations

    • Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada V5Z 4E6
    • Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada V6J 3Z6
    • Corresponding Author InformationCorresponding author. Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6.
    • ,
  • Torsten O. Nielsen, MD, PhD

      Affiliations

    • Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada V6J 3Z6
    • Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada V5Z 1M9
    • ,
  • Maggie C. Cheang, MMedSc

      Affiliations

    • Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada V6J 3Z6
    • ,
  • William D. Foulkes, MD, PhD

      Affiliations

    • Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada H2W 1S6

Received 8 October 2007 ,Revised 5 March 2008 ,Accepted 11 March 2008.

References 

  1. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752
  2. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–10874
  3. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100:8418–8423
  4. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–2502
  5. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–5374
  6. Foulkes WD, Brunet JS, Stefansson IM, et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 2004;64:830–835
  7. Signoretti S, Di Marcotullio L, Richardson A, et al. Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J Clin Invest. 2002;110:633–641
  8. Bartek J, Lukas J. Cell cycle. Order from destruction. Science. 2001;294:66–67
  9. Hunt KK, Keyomarsi K. Cyclin E as a prognostic and predictive marker in breast cancer. Semin Cancer Biol. 2005;15:319–326
  10. Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and survival in patients with breast cancer. N Engl J Med. 2002;347:1566–1575
  11. Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997;3:227–230
  12. Chappuis PO, Kapusta L, Begin LR, et al. Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer. J Clin Oncol. 2000;18:4045–4052
  13. Spataro VJ, Litman H, Viale G, et al. Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V. Cancer. 2003;97:1591–1600
  14. Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N, Slingerland JM. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc Natl Acad Sci U S A. 2000;97:9042–9046
  15. Donovan JC, Milic A, Slingerland JM. Constitutive MEK/MAPK activation leads to p27(Kip1) deregulation and antiestrogen resistance in human breast cancer cells. J Biol Chem. 2001;276:40888–40895
  16. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999;1:193–199
  17. Sonoda H, Inoue H, Ogawa K, et al. Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215–1220
  18. Makretsov N, Gilks CB, Coldman AJ, Hayes M, Huntsman D. Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer. Hum Pathol. 2003;34:1001–1008
  19. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. [see comment] Nat Med. 1998;4:844–847
  20. Parker RL, Huntsman DG, Lesack DW, et al. Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol. 2002;117:723–728
  21. Liu CL, Montgomery KD, Natkunam Y, et al. TMA-Combiner, a simple software tool to permit analysis of replicate cores on tissue microarrays. Mod Pathol. 2005;18:1641–1648
  22. Wang L, Shao ZM. Cyclin e expression and prognosis in breast cancer patients: a meta-analysis of published studies. Cancer Invest. 2006;24:581–587
  23. Han S, Park K, Bae BN, 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;83:241–247
  24. Rudolph P, Kuhling H, Alm P, 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;105:674–680
  25. Tan P, Cady B, Wanner M, et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res. 1997;57:1259–1263
  26. Traub F, Mengel M, Luck HJ, Kreipe HH, von Wasielewski R. Prognostic impact of Skp2 and p27 in human breast cancer. Breast Cancer Res Treat. 2006;99:185–191
  27. Keyomarsi K, Pardee AB. Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci U S A. 1993;90:1112–1116
  28. Chappuis PO, Donato E, Goffin JR, et al. Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment. Ann Oncol. 2005;16:735–742
  29. Kawamata N, Morosetti R, Miller CW, et al. Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. Cancer Res. 1995;55:2266–2269
  30. Ponce-Castaneda MV, Lee MH, Latres E, et al. p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. Cancer Res. 1995;55:1211–1214
  31. Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res. 2004;6:13–21
  32. Han S, Park K, Kim HY, Lee MS, Kim HJ, Kim YD. Reduced expression of p27Kip1 protein is associated with poor clinical outcome of breast cancer patients treated with systemic chemotherapy and is linked to cell proliferation and differentiation. Breast Cancer Res Treat. 1999;55:161–167
  33. Barbareschi M, van Tinteren H, Mauri FA, et al. p27(kip1) expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. Int J Cancer. 2000;89:236–241
  34. Barnes A, Pinder SE, Bell JA, et al. Expression of p27kip1 in breast cancer and its prognostic significance. J Pathol. 2003;201:451–459
  35. Leivonen M, Nordling S, Lundin J, von Boguslawski K, Haglund C. p27 expression correlates with short-term, but not with long-term prognosis in breast cancer. Breast Cancer Res Treat. 2001;67:15–22
  36. Dees EC, Orlowski RZ. Targeting the ubiquitin-proteasome pathway in breast cancer therapy. Future Oncol. 2006;2:121–135
  37. Cardoso F, Ross JS, Picart MJ, Sotiriou C, Durbecq V. Targeting the ubiquitin-proteasome pathway in breast cancer. Clin Breast Cancer. 2004;5:148–157
  38. Johnson KR, Fan W. Reduced expression of p53 and p21WAF1/CIP1 sensitizes human breast cancer cells to paclitaxel and its combination with 5-fluorouracil. Anticancer Res. 2002;22:3197–3204
  39. Smith ML, Seo YR. Sensitivity of cyclin E–overexpressing cells to cisplatin/taxol combinations. Anticancer Res. 2000;20:2537–2539

☆ This study examines a novel combination of breast cancer immunohistochemical biomarkers on a large tissue microarray with long follow-up. We show that this combination has prognostic value and is closely associated with the basal breast cancer phenotype.

☆☆ This work was supported by a grant from the Canadian Breast Cancer Research Alliance to WDF and TON. The Genetic Pathology Evaluation Centre is supported by an unrestricted educational grant from Sanofi-Aventis.

PII: S0046-8177(08)00134-2

doi: 10.1016/j.humpath.2008.03.004

Human Pathology
Volume 39, Issue 10 , Pages 1431-1437 , October 2008

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