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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

Abstract

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.

Keywords

References

  1. 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. https://doi.org/10.1007/s10549-011-1380-y
  2. Bennett LM (1999). Breast cancer: genetic predisposition and exposure to radiation. Mol Carcinog, 26, 143-9. https://doi.org/10.1002/(SICI)1098-2744(199911)26:3<143::AID-MC2>3.0.CO;2-S
  3. 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. https://doi.org/10.1186/1471-2407-5-81
  4. 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. https://doi.org/10.1038/bjc.1957.43
  5. 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. https://doi.org/10.1016/j.ygyno.2005.08.026
  6. 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. https://doi.org/10.1016/S0140-6736(01)06524-2
  7. 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. https://doi.org/10.1038/bjc.1997.526
  8. Dobrovic A, Simpfendorfer D (1997). Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res, 57, 3347-50.
  9. Gayther SA, Pharoah PD, Ponder BA (1998). The genetics of inherited breast cancer. J Mammary Gland Biol Neoplasia, 3, 365-76. https://doi.org/10.1023/A:1018779830743
  10. 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. https://doi.org/10.1093/annonc/mdq303
  11. Hofmann W, Schlag PM (2000). BRCA1 and BRCA2--breast cancer susceptibility genes. J Cancer Res Clin Oncol, 126, 487-96. https://doi.org/10.1007/s004320000140
  12. Hughes-Davies L ( 2 0 0 3 ) . The BRCA2-EMSY Connection:Implications for Breast and Ovarian Tumorigenesis. Cell, 115, 507-12. https://doi.org/10.1016/S0092-8674(03)00933-4
  13. 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. https://doi.org/10.1016/S0092-8674(03)00930-9
  14. Kenemans P, Verstraeten RA, Verheijen RH (2004). Oncogenic pathways in hereditary and sporadic breast cancer. Maturitas, 49, 34-43. https://doi.org/10.1016/j.maturitas.2004.06.005
  15. Kirkegaard T, Nielsen KV, Jensen LB, et al (2008). Genetic alterations of CCND1 and EMSY in breast cancers. Histopathology, 52, 698-705. https://doi.org/10.1111/j.1365-2559.2008.03007.x
  16. Kolahdoozan S, Sadjadi A, Radmard AR, Khademi H (2010). Five common cancers in Iran. Arch Iran Med, 13, 143-6.
  17. Kononen J, Bubendorf L, Kallioniemi A, et al (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 4, 844-7. https://doi.org/10.1038/nm0798-844
  18. 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. https://doi.org/10.1007/s10549-012-2051-3
  19. 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. https://doi.org/10.1172/JCI45014
  20. Livingston DM (2004). EMSY, a BRCA-2 partner in crime. Nat Med, 10, 127-8. https://doi.org/10.1038/nm0204-127
  21. 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.
  22. 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. https://doi.org/10.7314/APJCP.2012.13.6.2973
  23. McShane LM, Altman DG, Sauerbrei W, et al (2005). Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst, 97, 1180-4. https://doi.org/10.1093/jnci/dji237
  24. 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. https://doi.org/10.3109/15513815.2012.701266
  25. 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. https://doi.org/10.1126/science.7545954
  26. 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. https://doi.org/10.1038/modpathol.2010.84
  27. 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. https://doi.org/10.1007/s13402-011-0043-7
  28. 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. https://doi.org/10.1007/s00262-013-1463-1
  29. Mousavi SM, Gouya MM, Ramazani R, et al (2009). Cancer incidence and mortality in Iran. Ann Oncol, 20, 556-63.
  30. 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. https://doi.org/10.5812/ircmj.3631
  31. Mutch D, Denny L, Quinn M (2014). Hereditary gynecologic cancers. Int J Gynaecol Obstet, 24, 189-92.
  32. 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.
  33. 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. https://doi.org/10.1016/j.ejca.2013.06.006
  34. 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. https://doi.org/10.1002/ijc.25754
  35. Parkin DM, Bray F, Ferlay J, Pisani P (2001). Estimating the world cancer burden: Globocan 2000. Int J Cancer, 94, 153-6. https://doi.org/10.1002/ijc.1440
  36. Paul A, Paul S (2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci, 19, 605-18. https://doi.org/10.2741/4230
  37. Ponder BA (2001). Cancer genetics. Nature, 411, 336-41. https://doi.org/10.1038/35077207
  38. 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. https://doi.org/10.1158/1078-0432.CCR-03-0410
  39. 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.
  40. 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. https://doi.org/10.1016/0378-1119(94)00562-7
  41. 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. https://doi.org/10.1186/1746-1596-7-57
  42. 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. https://doi.org/10.1016/j.prp.2013.09.012
  43. 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.
  44. Venkitaraman AR (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell, 108, 171-82. https://doi.org/10.1016/S0092-8674(02)00615-3
  45. Wilkerson PM, Dedes KJ, Wetterskog D, et al (2011). Functional characterization of EMSY gene amplification in human cancers. J Pathol, 225, 29-42. https://doi.org/10.1002/path.2944
  46. Wooster R, Stratton MR (1995). Breast cancer susceptibility: a complex disease unravels. Trends Genet, 11, 3-5. https://doi.org/10.1016/S0168-9525(00)88974-X
  47. Yao J, Polyak K (2004). EMSY links breast cancer gene 2 to the 'Royal Family'. Breast Cancer Res, 6, 201-3. https://doi.org/10.1186/bcr916

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