Skip to main content

Advertisement

SpringerLink
Log in

EMSY and CCND1 amplification in familial breast cancer: from the Ontario site of the Breast Cancer Family Registry

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

EMSY is a putative oncogene amplified in a minority of breast carcinomas, its protein product interacts with and transcriptionally silences BRCA2. We hypothesized that breast tumors from BRCA2 mutation carriers would be less likely than other familial breast cancers to exhibit EMSY amplification. As EMSY is located on 11q13 in proximity to CCND1, an established breast cancer oncogene, we also examined the amplification of CCND1 in the same tumor cohort. Amplification of EMSY and CCND1 were examined in 58 BRCA1-associated, 64 BRCA2-associated, and 242 familial non-BRCA1/BRCA2 breast cancers using fluorescent in situ hybridization (FISH). All tumors had a centralized pathology review and underwent molecular phenotyping by immunohistochemical profiling on tissue microarrays (TMAs). Tumors with amplification of EMSY and/or CCND1 were compared with non-amplified tumors for morphological appearance, molecular subtype, and overall survival. EMSY amplification was detected in 8% of BRCA1-associated, 0% of BRCA2-associated, and 9% of familial non-BRCA1/BRCA2 breast tumors (P = 0.036). CCND1 was amplified in 4% of BRCA1-associated, 13% of BRCA2-associated and 21% of non-BRCA1/BRCA2 breast tumors (P = 0.054). EMSY was amplified independently of CCND1 in 38% of cases. EMSY amplification was associated with increased tumor stage only; whereas CCND1 amplification was associated with high tumor grade, ER positivity, and inversely associated with the basal-like phenotype. There was a trend toward worse overall survival in ER-positive non-BRCA1/BRCA2 familial breast cancer patients whose tumors exhibited EMSY and CCND1 co-amplification. BRCA2-associated breast tumors are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit EMSY amplification. BRCA1-associated breast cancers are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit CCND1 amplification. EMSY amplification does occur independently of CCND1 amplification in a minority of familial breast cancers, supporting its role as a possible breast cancer oncogene.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Merajver SD, Frank TS, Xu J et al (1995) Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer. Clin Cancer Res 1:539–544

    PubMed  CAS  Google Scholar 

  2. Turner NC, Reis-Filho JS, Russell AM et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26:2126–2132

    Article  PubMed  CAS  Google Scholar 

  3. Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814–819

    Article  PubMed  CAS  Google Scholar 

  4. Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423

    Article  PubMed  CAS  Google Scholar 

  5. Bane AL, Pinnaduwage D, Colby S et al (2009) Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast Cancer Res Treat 117:183–191

    Article  PubMed  CAS  Google Scholar 

  6. Lakhani SR, Reis-Filho JS, Fulford L et al (2005) Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11:5175–5180

    Article  PubMed  CAS  Google Scholar 

  7. Lancaster JM, Wooster R, Mangion J et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13:238–240

    Article  PubMed  CAS  Google Scholar 

  8. 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 76:1150–1156

    Article  PubMed  CAS  Google Scholar 

  9. Hughes-Davies L, Huntsman D, Ruas M et al (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115:523–535

    Article  PubMed  CAS  Google Scholar 

  10. van Hattem WA, Carvalho R, Li A et al (2008) Amplification of EMSY gene in a subset of sporadic pancreatic adenocarcinomas. Int J Clin Exp Pathol 1:343–351

    PubMed  Google Scholar 

  11. Brown LA, Irving J, Parker R et al (2006) Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas. Gynecol Oncol 100:264–270

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Peters G, Fantl V, Smith R et al (1995) Chromosome 11q13 markers and D-type cyclins in breast cancer. Breast Cancer Res Treat 33:125–135

    Article  PubMed  CAS  Google Scholar 

  14. Karlseder J, Zeillinger R, Schneeberger C et al (1994) Patterns of DNA amplification at band q13 of chromosome 11 in human breast cancer. Genes Chromosomes Cancer 9:42–48

    Article  PubMed  CAS  Google Scholar 

  15. Reis-Filho JS, Savage K, Lambros MB et al (2006) Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol 19(7):999–1009

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. John EM, Hopper JL, Beck JC et al (2004) The breast cancer family registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res 6:R375–R389

    Article  PubMed  Google Scholar 

  18. Tavassoli T, Devilee P (2003) Pathology & genetics. Tumours of the breast and female genital organs. IARC Press, Lyon

    Google Scholar 

  19. O’Malley FP, Pinder SE (2006) Breast pathology: a volume in the foundations in diagnostic pathology. Churchill Livingstone, New York

    Google Scholar 

  20. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410

    Article  PubMed  CAS  Google Scholar 

  21. Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    Article  PubMed  CAS  Google Scholar 

  22. Bane AL, Beck JC, Bleiweiss I et al (2007) BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol 31:121–128

    Article  PubMed  Google Scholar 

  23. Andrulis IL, Anton-Culver H, Beck J et al (2002) Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations. Hum Mutat 20:65–73

    Article  PubMed  CAS  Google Scholar 

  24. Youil R, Kemper BW, Cotton RG (1995) Screening for mutations by enzyme mismatch cleavage with T4 endonuclease VII. Proc Natl Acad Sci USA 92:87–91

    Article  PubMed  CAS  Google Scholar 

  25. Espinosa R 3rd, Le Beau MM (1997) Gene mapping by FISH. Methods Mol Biol 68:53–76

    PubMed  CAS  Google Scholar 

  26. Allred DC, Harvey JM, Berardo M et al (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    PubMed  CAS  Google Scholar 

  27. Harvey JM, Clark GM, Osborne CK et al (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481

    PubMed  CAS  Google Scholar 

  28. Wolff AC, Hammond ME, Schwartz JN et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131:18–43

    PubMed  CAS  Google Scholar 

  29. Mulligan AM, Pinnaduwage D, Bull SB et al (2008) Prognostic effect of basal-like breast cancers is time dependent: evidence from tissue microarray studies on a lymph node-negative cohort. Clin Cancer Res 14:4168–4174

    Article  PubMed  CAS  Google Scholar 

  30. Liu CL, Prapong W, Natkunam Y et al (2002) Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol 161:1557–1565

    Article  PubMed  CAS  Google Scholar 

  31. Liu CL, Montgomery KD, Natkunam Y et al (2005) TMA-combiner, a simple software tool to permit analysis of replicate cores on tissue microarrays. Mod Pathol 18:1641–1648

    PubMed  CAS  Google Scholar 

  32. Brown LA, Johnson K, Leung S et al (2009) Co-amplification of CCND1 and EMSY is associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers. Breast Cancer Res Treat 121(2):347–354

    Article  PubMed  Google Scholar 

  33. Kirkegaard T, Nielsen KV, Jensen LB et al (2008) Genetic alterations of CCND1 and EMSY in breast cancers. Histopathology 52:698–705

    Article  PubMed  CAS  Google Scholar 

  34. Rodriguez C, Hughes-Davies L, Valles H et al (2004) Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome. Clin Cancer Res 10:5785–5791

    Article  PubMed  CAS  Google Scholar 

  35. Barnes DM (1997) Cyclin D1 in mammary carcinoma. J Pathol 181:267–269

    Article  PubMed  CAS  Google Scholar 

  36. Butt AJ, McNeil CM, Musgrove EA et al (2005) Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer 12(Suppl 1):S47–S59

    Article  PubMed  CAS  Google Scholar 

  37. Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215–4224

    Article  PubMed  CAS  Google Scholar 

  38. Neuman E, Ladha MH, Lin N et al (1997) Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338–5347

    PubMed  CAS  Google Scholar 

  39. Zwijsen RM, Buckle RS, Hijmans EM et al (1998) Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev 12:3488–3498

    Article  PubMed  CAS  Google Scholar 

  40. Zwijsen RM, Wientjens E, Klompmaker R et al (1997) CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405–415

    Article  PubMed  CAS  Google Scholar 

  41. Courjal F, Cuny M, Simony-Lafontaine J et al (1997) Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res 57:4360–4367

    PubMed  CAS  Google Scholar 

  42. Zukerberg LR, Yang WI, Gadd M et al (1995) Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol 8:560–567

    PubMed  CAS  Google Scholar 

  43. Barbareschi M, Pelosio P, Caffo O et al (1997) Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression. Int J Cancer 74:171–174

    Article  PubMed  CAS  Google Scholar 

  44. Jirstrom K, Stendahl M, Ryden L et al (2005) Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 65:8009–8016

    PubMed  Google Scholar 

  45. Stendahl M, Kronblad A, Ryden L et al (2004) Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br J Cancer 90:1942–1948

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Seshadri R, Lee CS, Hui R et al (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 2:1177–1184

    PubMed  CAS  Google Scholar 

  48. Al-Kuraya K, Schraml P, Torhorst J et al (2004) Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 64:8534–8540

    Article  PubMed  CAS  Google Scholar 

  49. Bostner J, Ahnstrom Waltersson M, Fornander T et al (2007) Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene 26:6997–7005

    Article  PubMed  CAS  Google Scholar 

  50. Schuuring E, Verhoeven E, van Tinteren H et al (1992) Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res 52:5229–5234

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the participants and staff of the Ontario site of the Breast Cancer Family Registry. This work was supported by the Canadian Breast Cancer Foundation and the National Cancer Institute under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal investigators, including Cancer Care Ontario (U01 CA69467). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Breast Cancer Family Registry. This work was also supported by the Ontario Institute of Cancer Research.

Author information

Authors and Affiliations

  1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Anita L. Bane

  2. Department of Oncology, McMaster University, Hamilton, ON, Canada

    Anita L. Bane

  3. Department of Pathology, Rm 2F-211, Juravinski Hospital & Cancer Centre, 711 Concession Street, Hamilton, ON, L8V 1C3, Canada

    Anita L. Bane

  4. Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, Canada

    Anna Marie Mulligan & Frances P. O’Malley

  5. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Anna Marie Mulligan, Frances P. O’Malley & Irene L. Andrulis

  6. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Dushanthi Pinnaduwage & Irene L. Andrulis

  7. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Irene L. Andrulis

Authors
  1. Anita L. Bane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Marie Mulligan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dushanthi Pinnaduwage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frances P. O’Malley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene L. Andrulis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anita L. Bane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bane, A.L., Mulligan, A.M., Pinnaduwage, D. et al. EMSY and CCND1 amplification in familial breast cancer: from the Ontario site of the Breast Cancer Family Registry. Breast Cancer Res Treat 127, 831–839 (2011). https://doi.org/10.1007/s10549-011-1380-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1380-y

Keywords

Search

Navigation