Expression of EMSY, a Novel BRCA2-link Protein, is Associated with Lymph Node Metastasis and Increased Tumor Size in Breast Carcinomas

  • Madjd, Zahra (Oncopathology Research Center and Dep pathology, Faculty of medicine, Iran University of Medical Sciences) ;
  • Akbari, Mohammad Esmaeil (Cancer Research Center, Shahid Beheshti University of Medical Sciences) ;
  • Zarnani, Amir Hassan (Nanobiotechnology Research Center, Avicenna Research Institute, ACECR) ;
  • Khayamzadeh, Maryam (Cancer Research Center, Shahid Beheshti University of Medical Sciences) ;
  • Kalantari, Elham (Oncopathology Research Center and Dep pathology, Faculty of medicine, Iran University of Medical Sciences) ;
  • Mojtabavi, Nazanin (Department of Immunology, faculty of medicine, Iran University of Medical Sciences)
  • Published : 2014.02.28


Background: The EMSY gene encodes a BRCA2-binding partner protein that represses the DNA repair function of BRCA2 in non-hereditary breast cancer. Although amplification of EMSY gene has been proposed to have prognostic value in breast cancer, no data have been available concerning EMSY tissue expression patterns and its associations with clinicopathological features. Materials and Methods: In the current study, we examined the expression and localization pattern of EMSY protein by immunohistochemistry and assessed its prognostic value in a well-characterized series of 116 unselected breast carcinomas with a mean follow up of 47 months using tissue microarray technique. Results: Immunohistochemical expression of EMSY protein was detected in 76% of primary breast tumors, localized in nuclear (18%), cytoplasmic (35%) or both cytoplasmic and nuclear sites (23%). Univariate analysis revealed a significant positive association between EMSY expression and lymph node metastasis (p value=0.045) and larger tumor size (p value=0.027), as well as a non-significant relation with increased risk of recurrence (p value=0.088), whereas no association with patients' survival (log rank test, p value=0.482), tumor grade or type was observed. Conclusions: Herein, we demonstrated for the first time the immunostaining pattern of EMSY protein in breast tumors. Our data imply that EMSY protein may have impact on clinicipathological parameters and could be considered as a potential target for breast cancer treatment.


  1. 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, 5785-91.
  2. Parkin DM, Bray F, Ferlay J, Pisani P (2001). Estimating the world cancer burden: Globocan 2000. Int J Cancer, 94, 153-6.
  3. Paul A, Paul S (2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci, 19, 605-18.
  4. Ponder BA (2001). Cancer genetics. Nature, 411, 336-41.
  5. Sadjadi A, Nouraie M, Mohagheghi MA, et al (2005). Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev, 6, 359-63.
  6. Schuuring E (1995). The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes a review. Gene, 159, 83-96.
  7. Sotoudeh K, Hashemi F, Madjd Z, et al (2012). The clinicopathologic association of c-MET overexpression in Iranian gastric carcinomas; an immunohistochemical study of tissue microarrays. Diagn Pathol, 7, 57.
  8. Taeb J, Asgari M, Abolhasani M, Farajollahi MM, Madjd Z (2014). Expression of prostate stem cell antigen (PSCA) in prostate cancer: A tissue microarray study of Iranian patients. Pathol Res Pract, 210, 18-23.
  9. Van Hattem WA, Carvalho R, Li A, Offerhaus GJ, Goggins M (2008). Amplification of EMSY gene in a subset of sporadic pancreatic adenocarcinomas. Int J Clin Exp Pathol, 1, 343-51.
  10. Venkitaraman AR (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell, 108, 171-82.
  11. Wilkerson PM, Dedes KJ, Wetterskog D, et al (2011). Functional characterization of EMSY gene amplification in human cancers. J Pathol, 225, 29-42.
  12. Mousavi SM, Gouya MM, Ramazani R, et al (2009). Cancer incidence and mortality in Iran. Ann Oncol, 20, 556-63.
  13. Moelans CB, De Weger RA, Monsuur HN, Vijzelaar R, Van Diest PJ (2010). Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. Mod Pathol, 23, 1029-39.
  14. Moelans CB, De Weger RA, Monsuur HN, Maess AH, Van Diest PJ (2011). Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study. Cell Oncol, 34, 475-82.
  15. Mohsenzadegan M, Madjd Z,Asgari M, et al (2013). Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis. Cancer Immunol Immunother, 62, 1609-18.
  16. Movahedi M, Haghighat S, Khayamzadeh M, et al (2012). Survival rate of breast cancer based on geographical Variation in Iran, a National Study. Iran Red Crescent Med J, 14, 798-804.
  17. Mutch D, Denny L, Quinn M (2014). Hereditary gynecologic cancers. Int J Gynaecol Obstet, 24, 189-92.
  18. Nelson HD, Pappas M, Zakher B, et al (2014). Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med, 160, 255-66.
  19. Nurminen R, Lehtonen R, Auvinen A, et al (2013). Fine mapping of 11q13.5 identifies regions associated with prostate cancer and prostate cancer death. Eur J Cancer, 49, 3335-43.
  20. Nurminen R, Wahlfors T, Tammela TL, Schleutker J (2011). Identification of an aggressive prostate cancer predisposing variant at 11q13. Int J Cancer, 129, 599-606.
  21. Lehmann BD, Bauer JA, Chen X, et al (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest, 121, 2750-67.
  22. Kolahdoozan S, Sadjadi A, Radmard AR, Khademi H (2010). Five common cancers in Iran. Arch Iran Med, 13, 143-6.
  23. Kononen J, Bubendorf L, Kallioniemi A, et al (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 4, 844-7.
  24. Kornegoor R, Moelans CB, Verschuur-Maes AH, et al (2012). Oncogene amplification in male breast cancer: analysis by multiplex ligation-dependent probe amplification. Breast Cancer Res Treat, 135, 49-58.
  25. Livingston DM (2004). EMSY, a BRCA-2 partner in crime. Nat Med, 10, 127-8.
  26. Madjd Z, Karimi A, Molanae S, Asadi-Lari M (2011). BRCA1 Protein Expression Level and CD44(+) Phenotype in Breast Cancer Patients. Cell J, 13, 155-62.
  27. Madjd Z, Ramezani B, Molanae S, Asadi-Lari M (2012). High Expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas. Asian Pac J Cancer Prev, 13, 2973-8.
  28. McShane LM, Altman DG, Sauerbrei W, et al (2005). Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst, 97, 1180-4.
  29. Mehrazma M, Madjd Z, kalantari E, et al (2013). Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. Fetal Pediatr Pathol, 32, 192-204.
  30. Miki Y, Swensen J, Shattuck-Eidens D, et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266, 66-71.
  31. Dobrovic A, Simpfendorfer D (1997). Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res, 57, 3347-50.
  32. Collaborative Group on Hormonal Factors in Breast Cancer (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet, 358, 1389-99.
  33. 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, 1150-6.
  34. Gayther SA, Pharoah PD, Ponder BA (1998). The genetics of inherited breast cancer. J Mammary Gland Biol Neoplasia, 3, 365-76.
  35. Harirchi I, Kolahdoozan S, Karbakhsh M, et al (2011). Twenty years of breast cancer in Iran: downstaging without a formal screening program. Ann Oncol, 22, 93-7.
  36. Hofmann W, Schlag PM (2000). BRCA1 and BRCA2--breast cancer susceptibility genes. J Cancer Res Clin Oncol, 126, 487-96.
  37. Hughes-Davies L ( 2 0 0 3 ) . The BRCA2-EMSY Connection:Implications for Breast and Ovarian Tumorigenesis. Cell, 115, 507-12.
  38. Hughes-Davies L, Huntsman D, Ruas M, et al (2003). EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell, 115, 523-35.
  39. Kenemans P, Verstraeten RA, Verheijen RH (2004). Oncogenic pathways in hereditary and sporadic breast cancer. Maturitas, 49, 34-43.
  40. Kirkegaard T, Nielsen KV, Jensen LB, et al (2008). Genetic alterations of CCND1 and EMSY in breast cancers. Histopathology, 52, 698-705.
  41. Bane AL, Mulligan AM, Pinnaduwage D, O'Malley FP, Andrulis IL (2011). EMSY and CCND1 amplification in familial breast cancer: from the Ontario site of the Breast Cancer Family Registry. Breast Cancer Res Treat, 127, 831-9.
  42. Bennett LM (1999). Breast cancer: genetic predisposition and exposure to radiation. Mol Carcinog, 26, 143-9.<143::AID-MC2>3.0.CO;2-S
  43. Benusiglio PR, Lesueur F, Luccarini C, et al (2005). Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs. BMC Cancer, 5, 81.
  44. Bloom HJ, Richardson WW (1957). Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer, 11, 359-77.
  45. 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, 264-70.
  46. Wooster R, Stratton MR (1995). Breast cancer susceptibility: a complex disease unravels. Trends Genet, 11, 3-5.
  47. Yao J, Polyak K (2004). EMSY links breast cancer gene 2 to the 'Royal Family'. Breast Cancer Res, 6, 201-3.

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