Advertisement

Tumor Biology

, Volume 34, Issue 3, pp 1569–1578 | Cite as

Prognostic value of bcl-2 expression among women with breast cancer in Libya

  • Eramah Ermiah
  • Abdelbaset Buhmeida
  • Ben Romdhane Khaled
  • Fathi Abdalla
  • Nada Salem
  • Seppo Pyrhönen
  • Yrjö Collan
Research Article

Abstract

We studied the association of the immunohistochemical bcl-2 expression in Libyan breast cancer with clinicopathological variables and patient outcome. Histological samples from 170 previously untreated primary Libyan breast carcinoma patients were examined. In immunohistochemistry, the NCL-l-bcl-2-486 monoclonal antibody was used. Positive expression of bcl-2 was found in 106 patients (62.4 %). The bcl-2 expression was significantly associated with estrogen receptor (p < 0.0001) and progesterone receptor positive tumors (p = 0.002), small tumor size (p < 0.0001), low tumor grade (p < 0.0001), negative axillary lymph nodes (p < 0.0001), early stages (p = 0.001), and low risk of metastasis (p < 0.0001). Positive expression was also associated with older patients (>50 years; p = 0.04). Histological subtypes and family history of breast cancer did not have significant relationship with bcl-2. Patients with positive expression of bcl-2 had lower recurrence rate than bcl-2-negative patients and better survival after median follow-up of 47 months. Patients with high bcl-2 staining were associated with the best survival. The role of bcl-2 as an independent predictor of disease-specific survival was assessed in a multivariate survival (Cox) analysis, including age, hormonal status, recurrence, histological grade, and clinical stage variables. Bcl-2 (p < 0.0001) and clinical stage (p = 0.016) were independent predicators of disease-specific survival. For analysis of disease-free survival, the same variables were entered to the model and only bcl-2 proved to be an independent predictor (p = 0.002). Patients with positive expression of bcl-2 were associated with low grade of malignancy, with lower recurrence rate, with lower rate of death, and with longer survival time. Bcl-2 is an independent predictor of breast cancer outcome, and it provides useful prognostic information in Libyan breast cancer. Thus, it could be used with classical clinicopathological factors to improve patient selection for therapy.

Keywords

bcl-2 expression Libyan female breast cancer Prognosis 

Notes

Acknowledgments

The authors acknowledge the Libyan Health Ministry for financing the visit of Dr. Ermiah to the Departments of Pathology and Oncology, University of Turku, and Turku University Hospital, Finland. We also wish to thank the National Oncology Institute, Sabratha, Libya for support in collecting the data and providing the research facilities.

Conflict of interest

None

References

  1. 1.
    Abussa A. Hospital cancer registry annual report. Sabratha, Libya: African Oncology Institute; 2007. p. 18–20.Google Scholar
  2. 2.
    El Mistiri M, Verdecchia A, Rashid I, El Sahli N, El Mangush M, Federico M. Cancer incidence in eastern Libya: the first report from the Benghazi Cancer Registry, 2003. Int J Cancer. 2007;120(2):392–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Abulkhair O, Saghir N, Sedky L, et al. Modification and implementation of NCCN guidelines on breast cancer in the Middle East and North Africa region. J Natl Compr Canc Netw. 2010;8 Suppl 3:S8–S15.PubMedGoogle Scholar
  4. 4.
    Stapleton JM, Mullan PB, Dey S, et al. Patient-mediated factors predicting early- and late-stage presentation of breast cancer in Egypt. Psycho-Oncology. 2011;20(5):532–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Boder J, Abdalla F, Elfageih M, et al. Breast cancer patients in Libya: comparison with European and central African patients. Oncology Letters. 2011;2:323–30.PubMedGoogle Scholar
  6. 6.
    Galea MH, Blamey RW, Elson CE, Ellis IO. The Nottingham Promostic Index in primary breast cancer. Breast Cancer Res Treat. 1992;22:207–19.PubMedCrossRefGoogle Scholar
  7. 7.
    Kumar R, Vadlamudi RK, Adam L. Apoptosis in mammary glande and cancer. Endocrine-Related Cancer. 2000;7:257–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Krajewski S, Krajewski M, Turner BC, et al. Prognostic significance of apoptosis regulators in breast cancer. Endocrine-Related Cancer. 1999;6:29–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Arun B, Kilic G, Yen C, et al. Correlation Bcl-2 and p53 expression in primary breast tumors and corresponding metastatic lymph nodes. Cancer. 2003;98(12):2554–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Adms JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;28:1322–6.CrossRefGoogle Scholar
  11. 11.
    Hermine O, Hajoun C, Lepage E, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Group d Etude des Lymphomes de l Adulte (GELA). Blood. 1996;87:265–72.PubMedGoogle Scholar
  12. 12.
    Callagy GM, Pharoah PD, Pinder SE, et al. Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index. Cancer Res. 2006;12:2468–75.Google Scholar
  13. 13.
    Milano A, Lago LD, Sotiriou C, et al. What clinicians need to know about antioestrogen resistance in breast cancer therapy? Eur J Cancer. 2006;42:2696–705.CrossRefGoogle Scholar
  14. 14.
    Lipponen P, Pietilainen T, Kosma VM, Aaltomaa S, Eskelinen M, Syrjanen K. Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis. J Pathol. 1995;177:49–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Jager JJ, Jansen RLH, Arends JW. Clinical relevance of apoptosis markers in breat cancer not yet clear. Apoptosis. 2002;7:361–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Daidone MG, Luisi A, Veneroni S, et al. Clinical studies of bcl-2 and treatment benefit in breast cancer patients. Endocr Relat Cancer. 1999;6:61–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Le MG, Mathieu M-C, Douc-Rasy S, et al. c-myc, p53 and bcl-2, apoptosis-related genes in infiltrating breast carcinomas: evidence of a link between bcl-2 protein over-expression and a lower risk of metastasis and death in operable patients. Int J Cancer. 1999;84:562–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Silvestrini R, Benini E, Veneroni S, et al. P53 and bcl-2 expression correlated with clinical outcome in series of node-positive breast cancer patients. J Clin Oncol. 1996;14(5):1604–10.PubMedGoogle Scholar
  19. 19.
    Callagy GM, Webber MJ, Pharoah PD, Caldas C. Met-analysis confirm BCL2 is an independent prognostic marker in breast cancer. BMC Cancer. 2008;8:153.PubMedCrossRefGoogle Scholar
  20. 20.
    Dawson S-J, Makretsov N, Blows FM, et al. BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103:668–75.PubMedCrossRefGoogle Scholar
  21. 21.
    AJCC: 5th Edition AJCC Cancer Staging Manual. Philadelphia: Lippincott-Raven; 1997.Google Scholar
  22. 22.
    Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.PubMedGoogle Scholar
  23. 23.
    Zhang G-J, Kimijima I, Abe R, et al. Correlation between the expression of apoptosis-related bcl-2 and p53 oncoprotein and the carcinogenesis and progression of breast cancer. Clin Cancer Res. 1997;3:2329–35.PubMedGoogle Scholar
  24. 24.
    Sorlie T, Perou CM, Tibshirani R, Eystein Lonning P, Borresen-Dale AL, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implication. Proc Natl Acad Sci USA. 2001;98:10869–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Trere D, Montanaro L, Ceccarelli C, et al. Prognostic relevance of a novel semiquantitative classification of Bcl3 immunohistochemical expression in human infiltrating ductal carcinomas of the breast. Annals Oncolog. 2007;18(6):1004–14.CrossRefGoogle Scholar
  26. 26.
    Nadler Y, Camp RL, Giltnane JM, et al. Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer. Breast Cancer Res. 2008;10(35):1186.Google Scholar
  27. 27.
    Van Slooten HJ, Clahsen PC, van Dierendonck JH, et al. Expression of bcl-2 in node-negative breast cancer is associated various prognostic factors, but does not predict response to oneccourse of perioperative. Br J Cancer. 1996;74:78–85.PubMedCrossRefGoogle Scholar
  28. 28.
    Bottini A, Berruit A, Bersiga A, et al. p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer. Clin Cancer Res. 2000;6:2751–8.PubMedGoogle Scholar
  29. 29.
    Tang S-C, Jessalyn B, Murphy S, et al. BAG-1 expression correlates with Bcl-2, p53, differentiation, estrogen and progesterogen receptors in invasive breast carcinoma. Breast Cancer Res Treat. 2004;84:203–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Kroger N, Milde-Langosch K, Iethof S, et al. Prognostic and predictive effects of immunohistochemical factors in high-risk primary breast cancer patients. Clin Cancer Res. 2006;12(1):159–68.PubMedCrossRefGoogle Scholar
  31. 31.
    Malamou-Mitsi V, Gogas H, Dafni U, et al. Evaluation of the prognostic and predictive value of p53 andBcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy. Annals of Oncol. 2006;17(10):1504–11.CrossRefGoogle Scholar
  32. 32.
    Zinkel S, Gross A, Yang E. Bcl-2 family in DNA damage and cell cycle control. Cell Death Differ. 2006;13:1351–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Gee JM, Robertson JRR, Ellis IO. Immunocytochemical localization of Bcl-2 protien in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. Int J Cancer. 2006;5:619–28.Google Scholar
  34. 34.
    Freedman R, Winer E. Adjuvant therapy for menopusal women with endocrine-sensetive breast cancer. Breast. 2010;19:69–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Linke SP, Bremer TM, Herold CD, et al. A multimarker model to predict outcome in tamoxifen-treated breast cancer patients. Clin Canc Res. 2006;15:1175–83.CrossRefGoogle Scholar
  36. 36.
    Kymionis GD, Konstadoulakis MM, Dimitrakakis CE, et al. Can expression of apptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients? Surg Res. 2001;99(2):161–8. Abstract.CrossRefGoogle Scholar
  37. 37.
    Hun Lee K, Ah lm S, Youn Oh D, et al. Progmostic significance of Bcl-2 expression in stage lll breast cancer patients who had receivef doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy. BMC Cancer. 2007;7:63–70.CrossRefGoogle Scholar
  38. 38.
    Koman IE, Gurova KV, Kwek SS, et al. Apoptosis inhibitor as a suppressor of tumor progression: expression of Bcl-2 eliminates selective advantages for p53-deficient cells in the tumor. Canc Biol Ther. 2002;1(1):39–44.Google Scholar
  39. 39.
    Reed JC, Miyashita T, Takayama S, et al. Bcl-2 family proteins: regulators of cell death involved in the pathogenesis of cancer and resistance to therapy. J Cell Biochem. 1996;60:23–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Jaattela M, Benedict M, Tewari M, Shayman JA, Dixit VM. Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast cancer cells. Oncogene. 1995;10:2297–305.PubMedGoogle Scholar
  41. 41.
    Song RX, Mor G, Naftolin F, et al. Effect of long-term estrogen deprivation on apoptotic response of breast cancer cells to 17 beta-estradiol. J Natl Cancer Inst. 2001;93:1714–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Jordan VC, Liu H, Dardes R. Re: Effect of long-term estrogen deprivation on apoptotic response of breast cancer cells to 17 beta-estradiol and the two faces of Janus: sex steroids as mediators of both cell proliferation and cell death. J Natl Cancer Inst. 2002;94:1173–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Teixeira C, Reed JC, Pratt MA. Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. Cancer Res. 1995;55:3902–7.PubMedGoogle Scholar
  44. 44.
    Zhang GJ, Tsuda H, Adachi I, Fukutomi T, Yammamoto H, Hirohashi S. Prognostic indicators for breast cancer patients with one to three regional lymph node metastase, with special reference to alteration in expression levels of bcl-2, p53 and c-erb B-2 protiens. Jpn. J Clin. 1997;27:371–7.CrossRefGoogle Scholar
  45. 45.
    Bukhoim IR, Bukholm G, Nesland JM. Reduced expression both Bax and Bcl-2 is idependently associated with lymph node metastasis in human breast carcinomas. APMIS. 2002;110:214–20.CrossRefGoogle Scholar
  46. 46.
    Alis Dema, Simona Dragan, Elena Lazar, Danina Munteanu, Sorina Taban, Codruta Lzureanu, T. Nicola, S. Dema. Bcl-2 expression in primary breast carcinomas: correlation with other prognostic factors. Nr. 1-2/2008; pp. 65–71.Google Scholar
  47. 47.
    Daidone MG, Coradini D, Martelli G, et al. Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit Rev Oncol Hemat. 2003;45:313–25.CrossRefGoogle Scholar
  48. 48.
    Yu B, Sun X, Hong-yan S, et al. J Exp Clin Res. 2010;29:107.CrossRefGoogle Scholar
  49. 49.
    Ermiah E, Abdala F, Buhmeida A, et al. Prognostic significance of DNA image cytometry in Libyan breast cancer. Oncology. 2012;83:165–76.PubMedCrossRefGoogle Scholar
  50. 50.
    Jalava P, Collan Y, Kuopio T, Juntti-patinen L, Kronqvist P. Bcl-2 immunostaining: a way to finding unresponsive postmenopausal N + breast cancer patients. Anti Cancer Res. 2000;20:1213–20.Google Scholar
  51. 51.
    Olopade OI, Fakenthal JD, Dunston G, et al. Breast cancer genetics in African Americans. Cancer. 2003;97:236–45.PubMedCrossRefGoogle Scholar
  52. 52.
    Loo LW, Wang Y, Flynn EM, et al. Genome-wide copy number alteration in subtypes of invasive breast cancers in young white and African Americans women. Breast Canc Res Treat. 2011;127:297–308.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Eramah Ermiah
    • 1
    • 2
  • Abdelbaset Buhmeida
    • 3
  • Ben Romdhane Khaled
    • 4
  • Fathi Abdalla
    • 5
  • Nada Salem
    • 6
  • Seppo Pyrhönen
    • 1
  • Yrjö Collan
    • 7
  1. 1.Department of OncologyUniversity of Turku and Turku University HospitalTurkuFinland
  2. 2.Department of OncologyNational Cancer InstituteSabrathaLibya
  3. 3.Center of Excellence in Genomic Medicine ResearchKing Abdul-Aziz UniversityJeddahSaudi Arabia
  4. 4.Department of PathologySalah Azaiz Cancer InstituteTunisTunisia
  5. 5.Department of PathologyMisurata Cancer InstituteMisurataLibya
  6. 6.Department of BiochemistryKing Abdul-Aziz UniversityJeddahSaudi Arabia
  7. 7.Department of PathologyUniversity of Turku and Turku University HospitalTurkuFinland

Personalised recommendations