Skip to main content

Co-amplification of CCND1 and EMSY is associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers

Breast Cancer Research and Treatment volume 121, pages 347–354 (2010)Cite this article

Abstract

Amplification of chromosome 11q13 is commonly seen in breast carcinomas and candidate genes from this region include CCND1 and EMSY. Here, we investigate the prognostic significance of CCND1 and EMSY amplification in a large series of breast carcinomas and in BRCA1 and BRCA2 mutation positive breast cancers. Amplification of CCND1 and EMSY was assessed by fluorescent in situ hybridization. Both CCND1 and EMSY amplifications were associated with a significantly worse outcome in ER-positive patients treated with tamoxifen only, in contrast to nonamplified tumors (P = 8.55 × 10−4 and P = 8.35 × 10−5, respectively). In multivariable Cox models, which included standard prognostic markers, co-amplification of CCND1 and EMSY was significantly more predictive of outcome than was amplification of either gene alone or neither gene amplified in ER-positive tamoxifen-treated patients (P = 5.47 × 10−5). EMSY gene amplification was a significantly less common event in BRCA2 mutation carriers as compared to BRCA1 mutation carriers (9 versus 24%, respectively). In contrast, CCND1 amplification occurred at a similar frequency in both BRCA1 and BRCA2 breast cancers (22 versus 18%, respectively). In summary, co-amplification of CCND1 and EMSY identified a poor prognostic subset of ER-positive tamoxifen-treated patients. In addition, EMSY amplification occurred at a lower frequency in BRCA2 mutation carriers providing evidence to support EMSY amplification as a somatic surrogate for BRCA2 loss in sporadic breast cancer.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Peters G, Fantl V, Smith R, Brookes S, Dickson C (1995) Chromosome 11q13 markers and D-type cyclins in breast cancer. Breast Cancer Res Treat 33(2):125–135

    Article  CAS  PubMed  Google Scholar 

  2. Schwab M (1998) Amplification of oncogenes in human cancer cells. Bioessays 20(6):473–479

    Article  CAS  PubMed  Google Scholar 

  3. Bekri S, Adelaide J, Merscher S, Grosgeorge J, Caroli-Bosc F, Perucca-Lostanlen D, Kelley PM, Pebusque MJ, Theillet C, Birnbaum D et al (1997) Detailed map of a region commonly amplified at 11q13–>q14 in human breast carcinoma. Cytogenet Cell Genet 79(1–2):125–131

    Article  CAS  PubMed  Google Scholar 

  4. Courjal F, Cuny M, Simony-Lafontaine J, Louason G, Speiser P, Zeillinger R, Rodriguez C, Theillet C (1997) Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res 57(19):4360–4367

    CAS  PubMed  Google Scholar 

  5. Karlseder J, Zeillinger R, Schneeberger C, Czerwenka K, Speiser P, Kubista E, Birnbaum D, Gaudray P, Theillet C (1994) Patterns of DNA amplification at band q13 of chromosome 11 in human breast cancer. Genes Chromosomes Cancer 9(1):42–48

    Article  CAS  PubMed  Google Scholar 

  6. Hui R, Ball JR, Macmillan RD, Kenny FS, Prall OW, Campbell DH, Cornish AL, McClelland RA, Daly RJ, Forbes JF et al (1998) EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene 17(8):1053–1059

    Article  CAS  PubMed  Google Scholar 

  7. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7(5):812–821

    Article  CAS  PubMed  Google Scholar 

  8. Ormandy CJ, Musgrove EA, Hui R, Daly RJ, Sutherland RL (2003) Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78(3):323–335

    Article  CAS  PubMed  Google Scholar 

  9. Champeme MH, Bieche I, Lizard S, Lidereau R (1995) 11q13 amplification in local recurrence of human primary breast cancer. Genes Chromosomes Cancer 12(2):128–133

    Article  CAS  PubMed  Google Scholar 

  10. Lammie GA, Peters G (1991) Chromosome 11q13 abnormalities in human cancer. Cancer Cells 3(11):413–420

    CAS  PubMed  Google Scholar 

  11. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8(8):2127–2133

    CAS  PubMed  Google Scholar 

  12. Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G (1994) Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54(7):1812–1817

    CAS  PubMed  Google Scholar 

  13. Bieche I, Olivi M, Nogues C, Vidaud M, Lidereau R (2002) Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays. Br J Cancer 86(4):580–586

    Article  CAS  PubMed  Google Scholar 

  14. Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J (1996) A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer 73(6):728–734

    CAS  PubMed  Google Scholar 

  15. Seshadri R, Lee CS, Hui R, McCaul K, Horsfall DJ, Sutherland RL (1996) Cyclin DI amplification is not associated with reduced overall survival in primary breast cancer but may predict early relapse in patients with features of good prognosis. Clin Cancer Res 2(7):1177–1184

    CAS  PubMed  Google Scholar 

  16. Kilker RL, Planas-Silva MD (2006) Cyclin D1 is necessary for tamoxifen-induced cell cycle progression in human breast cancer cells. Cancer Res 66(23):11478–11484

    Article  CAS  PubMed  Google Scholar 

  17. Jirstrom K, Stendahl M, Ryden L, Kronblad A, Bendahl PO, Stal O, Landberg G (2005) Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 65(17):8009–8016

    PubMed  Google Scholar 

  18. Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC, Kumar R (2000) Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 275(46):36238–36244

    Article  CAS  PubMed  Google Scholar 

  19. Schraml P, Schwerdtfeger G, Burkhalter F, Raggi A, Schmidt D, Ruffalo T, King W, Wilber K, Mihatsch MJ, Moch H (2003) Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma. Am J Pathol 163(3):985–992

    CAS  PubMed  Google Scholar 

  20. Brown LA, Irving J, Parker R, Kim H, Press JZ, Longacre TA, Chia S, Magliocco A, Makretsov N, Gilks B et al (2006) Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol Oncol 100(2):264–270

    Article  CAS  PubMed  Google Scholar 

  21. Brown LA, Kalloger SE, Miller MA, Shih I.e. M, McKinney SE, Santos JL, Swenerton K, Spellman PT, Gray J, Gilks CB et al (2008) Amplification of 11q13 in ovarian carcinoma. Genes Chromosomes Cancer 47(6):481–489

    Article  CAS  PubMed  Google Scholar 

  22. Balasenthil S, Barnes CJ, Rayala SK, Kumar R (2004) Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells. FEBS Lett 567(2–3):243–247

    Article  CAS  PubMed  Google Scholar 

  23. Bostner J, Ahnstrom Waltersson M, Fornander T, Skoog L, Nordenskjold B, Stal O (2007) Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene 26(49):6997–7005

    Article  CAS  PubMed  Google Scholar 

  24. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B et al (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115(5):523–535

    Article  CAS  PubMed  Google Scholar 

  25. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14(5):1368–1376

    Article  CAS  PubMed  Google Scholar 

  26. Rodriguez C, Hughes-Davies L, Valles H, Orsetti B, Cuny M, Ursule L, Kouzarides T, Theillet C (2004) Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome. Clin Cancer Res 10(17):5785–5791

    Article  CAS  PubMed  Google Scholar 

  27. Kirkegaard T, Nielsen KV, Jensen LB, Campbell FM, Muller S, Tovey SM, Brown S, Cooke TG, Bartlett JM (2008) Genetic alterations of CCND1 and EMSY in breast cancers. Histopathology 52(6):698–705

    Google Scholar 

  28. Holm C, Rayala S, Jirstrom K, Stal O, Kumar R, Landberg G (2006) Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J Natl Cancer Inst 98(10):671–680

    CAS  PubMed  Article  Google Scholar 

  29. Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122

    Article  CAS  PubMed  Google Scholar 

  30. Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Seal S, Barfoot R, Collins N, Bignell G et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13(2):238–240

    Article  CAS  PubMed  Google Scholar 

  31. Sorlie T, Andersen TI, Bukholm I, Borresen-Dale AL (1998) Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases. Breast Cancer Res Treat 48(3):259–264

    Article  CAS  PubMed  Google Scholar 

  32. Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan BY (2000) BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 60(19):5329–5333

    CAS  PubMed  Google Scholar 

  33. Catteau A, Harris WH, Xu CF, Solomon E (1999) Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene 18(11):1957–1965

    Article  CAS  PubMed  Google Scholar 

  34. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(7):564–569

    Article  CAS  PubMed  Google Scholar 

  35. Geisler JP, Hatterman-Zogg MA, Rathe JA, Buller RE (2002) Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94(1):61–67

    CAS  PubMed  Google Scholar 

  36. Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW (2000) Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 21(9):1761–1765

    Article  CAS  PubMed  Google Scholar 

  37. Collins N, Wooster R, Stratton MR (1997) Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers. Br J Cancer 76(9):1150–1156

    CAS  PubMed  Google Scholar 

  38. Gras E, Cortes J, Diez O, Alonso C, Matias-Guiu X, Baiget M, Prat J (2001) Loss of heterozygosity on chromosome 13q12–q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors. Cancer 92(4):787–795

    Article  CAS  PubMed  Google Scholar 

  39. Hilton JL, Geisler JP, Rathe JA, Hattermann-Zogg MA, DeYoung B, Buller RE (2002) Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94(18):1396–1406

    CAS  PubMed  Google Scholar 

  40. King MC (2004) A novel BRCA2-binding protein and breast and ovarian tumorigenesis. N Engl J Med 350(12):1252–1253

    Article  CAS  PubMed  Google Scholar 

  41. Livingston DM (2004) EMSY, a BRCA-2 partner in crime. Nat Med 10(2):127–128

    Article  CAS  PubMed  Google Scholar 

  42. Vaziri SA, Tubbs RR, Darlington G, Casey G (2001) Absence of CCND1 gene amplification in breast tumours of BRCA1 mutation carriers. Mol Pathol 54(4):259–263

    Article  CAS  PubMed  Google Scholar 

  43. Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, Rodriguez S, Cigudosa JC, Diez O, Alonso C et al (2005) Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90(1):5–14

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Research funded by an operating grant from the CBCRI/CIHR awarded to DGH. DGH is a MSFHR senior scholar. The tissue microarray laboratory is supported by a research unit grant from the MSFHR and an unrestricted education grant from Sanofi-avenits Canada. We would like to thank Dr Ake Borg for contributing BRCA1 and BRCA2 mutation positive breast cancers for this study.

Author information

Affiliations

  1. Center for Translational and Applied Genomics, British Columbia Cancer Agency, 600 W. 10th Ave, Vancouver, BC, V5Z 4E6, Canada

    Lindsay A. Brown, Karynn Johnson & David G. Huntsman

  2. Genetic Pathology Evaluation Center, British Columbia Cancer Agency, Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Samuel Leung

  3. Departments of Pathology and Oncology, Jewish General Hospital and Program in Cancer Genetics, McGill University, 546 Pine Ave. West, Montreal, QC, H2W 1S6, Canada

    Tarek A. Bismar

  4. Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, Madrid, 28029, Spain

    Javier Benítez

  5. Program in Cancer Genetics, Gerald Bronfman Centre for Cancer Research, Department of Oncology, McGill University, 546 Pine Ave. West, Montreal, QC, H2W 1S6, Canada

    William D. Foulkes

Authors
  1. Lindsay A. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karynn Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tarek A. Bismar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Javier Benítez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David G. Huntsman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lindsay A. Brown.

Electronic supplementary material

Below is the link to the electronic supplementary material.

PDF 16 kb

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brown, L.A., Johnson, K., Leung, S. et al. Co-amplification of CCND1 and EMSY is associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers. Breast Cancer Res Treat 121, 347–354 (2010). https://doi.org/10.1007/s10549-009-0479-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0479-x

Keywords

  • Gene amplification
  • Breast cancer
  • Tissue microarray