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Breast Cancer Research and Treatment

, Volume 127, Issue 3, pp 831–839 | Cite as

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

  • Anita L. BaneEmail author
  • Anna Marie Mulligan
  • Dushanthi Pinnaduwage
  • Frances P. O’Malley
  • Irene L. Andrulis
Brief Report

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.

Keywords

Familial breast cancer EMSY amplification CCND1 amplification 

Notes

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.

References

  1. 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 1:539–544PubMedGoogle Scholar
  2. 2.
    Turner NC, Reis-Filho JS, Russell AM et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26:2126–2132PubMedCrossRefGoogle Scholar
  3. 3.
    Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4:814–819PubMedCrossRefGoogle Scholar
  4. 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 100:8418–8423PubMedCrossRefGoogle Scholar
  5. 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 117:183–191PubMedCrossRefGoogle Scholar
  6. 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 11:5175–5180PubMedCrossRefGoogle Scholar
  7. 7.
    Lancaster JM, Wooster R, Mangion J et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13:238–240PubMedCrossRefGoogle Scholar
  8. 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 76:1150–1156PubMedCrossRefGoogle Scholar
  9. 9.
    Hughes-Davies L, Huntsman D, Ruas M et al (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115:523–535PubMedCrossRefGoogle Scholar
  10. 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 1:343–351PubMedGoogle Scholar
  11. 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 100:264–270PubMedCrossRefGoogle Scholar
  12. 12.
    Schwab M (1998) Amplification of oncogenes in human cancer cells. Bioessays 20:473–479PubMedCrossRefGoogle Scholar
  13. 13.
    Peters G, Fantl V, Smith R et al (1995) Chromosome 11q13 markers and D-type cyclins in breast cancer. Breast Cancer Res Treat 33:125–135PubMedCrossRefGoogle Scholar
  14. 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 9:42–48PubMedCrossRefGoogle Scholar
  15. 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):999–1009PubMedCrossRefGoogle Scholar
  16. 16.
    Vaziri SA, Tubbs RR, Darlington G et al (2001) Absence of CCND1 gene amplification in breast tumours of BRCA1 mutation carriers. Mol Pathol 54:259–263PubMedCrossRefGoogle Scholar
  17. 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–R389PubMedCrossRefGoogle Scholar
  18. 18.
    Tavassoli T, Devilee P (2003) Pathology & genetics. Tumours of the breast and female genital organs. IARC Press, LyonGoogle Scholar
  19. 19.
    O’Malley FP, Pinder SE (2006) Breast pathology: a volume in the foundations in diagnostic pathology. Churchill Livingstone, New YorkGoogle Scholar
  20. 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 19:403–410PubMedCrossRefGoogle Scholar
  21. 21.
    Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847PubMedCrossRefGoogle Scholar
  22. 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 31:121–128PubMedCrossRefGoogle Scholar
  23. 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 20:65–73PubMedCrossRefGoogle Scholar
  24. 24.
    Youil R, Kemper BW, Cotton RG (1995) Screening for mutations by enzyme mismatch cleavage with T4 endonuclease VII. Proc Natl Acad Sci USA 92:87–91PubMedCrossRefGoogle Scholar
  25. 25.
    Espinosa R 3rd, Le Beau MM (1997) Gene mapping by FISH. Methods Mol Biol 68:53–76PubMedGoogle Scholar
  26. 26.
    Allred DC, Harvey JM, Berardo M et al (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168PubMedGoogle Scholar
  27. 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 17:1474–1481PubMedGoogle Scholar
  28. 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 131:18–43PubMedGoogle Scholar
  29. 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 14:4168–4174PubMedCrossRefGoogle Scholar
  30. 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 161:1557–1565PubMedCrossRefGoogle Scholar
  31. 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 18:1641–1648PubMedGoogle Scholar
  32. 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):347–354PubMedCrossRefGoogle Scholar
  33. 33.
    Kirkegaard T, Nielsen KV, Jensen LB et al (2008) Genetic alterations of CCND1 and EMSY in breast cancers. Histopathology 52:698–705PubMedCrossRefGoogle Scholar
  34. 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 10:5785–5791PubMedCrossRefGoogle Scholar
  35. 35.
    Barnes DM (1997) Cyclin D1 in mammary carcinoma. J Pathol 181:267–269PubMedCrossRefGoogle Scholar
  36. 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–S59PubMedCrossRefGoogle Scholar
  37. 37.
    Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23:4215–4224PubMedCrossRefGoogle Scholar
  38. 38.
    Neuman E, Ladha MH, Lin N et al (1997) Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338–5347PubMedGoogle Scholar
  39. 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 12:3488–3498PubMedCrossRefGoogle Scholar
  40. 40.
    Zwijsen RM, Wientjens E, Klompmaker R et al (1997) CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405–415PubMedCrossRefGoogle Scholar
  41. 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 57:4360–4367PubMedGoogle Scholar
  42. 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 8:560–567PubMedGoogle Scholar
  43. 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 74:171–174PubMedCrossRefGoogle Scholar
  44. 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 65:8009–8016PubMedGoogle Scholar
  45. 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 90:1942–1948PubMedCrossRefGoogle Scholar
  46. 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 86:580–586PubMedCrossRefGoogle Scholar
  47. 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 2:1177–1184PubMedGoogle Scholar
  48. 48.
    Al-Kuraya K, Schraml P, Torhorst J et al (2004) Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 64:8534–8540PubMedCrossRefGoogle Scholar
  49. 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 26:6997–7005PubMedCrossRefGoogle Scholar
  50. 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 52:5229–5234PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Anita L. Bane
    • 1
    • 2
    • 3
    Email author
  • Anna Marie Mulligan
    • 4
    • 5
  • Dushanthi Pinnaduwage
    • 6
  • Frances P. O’Malley
    • 4
    • 5
  • Irene L. Andrulis
    • 5
    • 6
    • 7
  1. 1.Department of Pathology and Molecular MedicineMcMaster UniversityHamiltonCanada
  2. 2.Department of OncologyMcMaster UniversityHamiltonCanada
  3. 3.Department of Pathology, Rm 2F-211Juravinski Hospital & Cancer CentreHamiltonCanada
  4. 4.Department of Laboratory MedicineSt. Michael’s HospitalTorontoCanada
  5. 5.Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  6. 6.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  7. 7.Department of Molecular GeneticsUniversity of TorontoTorontoCanada

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