Expression of Bax and Bcl-2 in Tumour Cells and Blood Vessels of Breast Cancer and their Association with Angiogenesis and Hormonal Receptors

  • Jaafar, Hasnan (Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Abdullah, Suhaila (Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Murtey, Mogana Das (Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Idris, Fauziah M. (Department of Medical Microbiology, School of Medical Sciences, Universiti Sains Malaysia)
  • Published : 2012.08.31


A total of 96 cases of invasive breast ductal carcinoma were examined for immunohistochemical expression of Bax and Bcl-2 in the epithelial tumor cells and endothelial cells of the blood vessels. We also investigated the association between both proteins in the epithelium in relation to tumor characteristics such as tumor size, grade, lymph node involvement, microvessel density (MVD), hormonal receptors expression and c-erbB-2 overexpression. Bax expression showed a significant association between tumor and endothelial cells (p<0.001) while Bcl-2 expression in tumor cells was inversely associated with that in the endothelial cells (p<0.001). Expression of Bcl-2 in tumor cells was strongly associated with expression of estrogen and progesterone receptors (p=0.003 and p=0.004, respectively). In addition, intratumoral MVD was significantly higher than peritumoral MVD (p<0.001) but not associated with Bax or Bcl-2 expression and other tumor characteristics. We concluded that the number of endothelial cells undergoing apoptosis was in direct linkage with the number of apoptotic tumor cells. Anti-apoptotic activity of the surviving tumor cells appears to propagate cancer progression and this was influenced by the hormonal status of the cells. Tumor angiogenesis was especially promoted in the intratumoral region and angiogenesis was independent of anti-apoptotic activity.



  1. Affara MB, Dunmore C, Savoie S, et al (2007). Understanding endothelial cell apoptosis:what can the transcriptome, glycome and proteome reveal? Phil Trans R Soc B, 362 1469-87.
  2. Allred DC, Harvey JM, Berardo M, Clark GM (1998). Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol, 11, 155-68.
  3. Al-Maoundhri M, Nirmala V, Al-Mawaly K, et al (2003). Significance of p53, Bcl-2, and HER-2/neu protein expression in Omani Arab females with breast cancer, Pathol Oncol Res, 9, 226-31.
  4. Axelsson K, Ljung BM, Moore DH, et al (1995). Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma, J Natl Cancer Inst, 87, 997-1008.
  5. Baccouche S, Daoud J, Frikha M, et al (2003) Immunohistochemical status of p53, MDM2, bcl2, bax, and ER in invasive ductal breast carcinoma in Tunisian patients, Ann N Y Acad Sci, 1010, 752-63.
  6. Carmeliet P, Dor Y, Herbert JM, et al (1998). Role of HIF- 1alpha in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature 394 485-490. Erratum in Nature, 395, 525.
  7. Carmeliet P, Lampugnani MG, Moons L, et al (1999). Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell, 98, 147-57.
  8. DAKO HercepTestTM for Immunoenzymatic Staining (1999). (Packge insert) DAKO A/S, Glastrup, Denmark.
  9. Djonov V, Andres AC, Ziemiecki A (2001). Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc Res Tech, 52, 182-9.<182::AID-JEMT1004>3.0.CO;2-M
  10. Folkman J (2003). Angiogenesis and apoptosis. Seminar Cancer Biol, 13, 159-67.
  11. Frierson HF Jr, Wolber RA, Berean KW, et al (1995). Interobserver reproducibility of the Notiingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol, 103, 195-8
  12. Giorgadze TA, Baloch ZW, Pasha T, Zhang PJ, LiVolsi VA (2005). Lymphatic and blood vessel density in the follicular patterned lesions of thyroid, Mod Pathol, 18, 1424-31.
  13. Gompel A, Somai S, Chaout M (2000). Hormonal regulation of apoptosis in breast cells and tissues, Steroids, 65, 593-8.
  14. Hanahan D, Folkman J (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353-64.
  15. Harada T, Kaponis A, Iwabe T, et al (2004). Apoptosis in human endometrium and endometriosis. Hum Reprod Update 10 29-38.
  16. Hasnan J, Yusof MI, Damitri TD, et al (2010). Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singapore Med J, 51 50-5.
  17. Holash J, Wiegand SJ, Yancopoulos GD (1999). New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene, 18, 5356-62
  18. Holmgren L, O'Reilly MS, Folkman J (1995). Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med, 1, 149-53.
  19. Intengan HD, Schiffrin EL (2001). Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension, 38, 581-7.
  20. Jan-Show C, Chiun-Sheng H, King-jen C (1998). The prognostic significance of tumor angiogenesis in Taiwanese patients with invasive ductal breast carcinomas, Cancer Letters, 134, 7-14.
  21. Kahlos K, Soini Y, Paakko P, et al (2000). Proliferation, apoptosis, and manganese superoxide dismutase in malignant mesothelioma. Int J Cancer, 88, 37-43.<37::AID-IJC6>3.0.CO;2-3
  22. Karelia NH, Patel DD, Balar DB, et al (1997). Prognostic significance of tumor angiogenesis in advanced breast carcinoma: an Indian experience. Neoplasma, 44, 163-6.
  23. Kebers F, Lewalle JM, Desreux J et al (1998). Induction of endothelial cell apoptosis by solid tumor cells. Experimental Cell Res, 240, 197-205
  24. Kerr JFR, Wyllie AH, Currie AR (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26, 239-57
  25. Kobayashi S, Iwase H, Ito Y, et al (1997). Clinical significance of Bcl-2 gene expression in human breast cancer tissues, Breast Cancer Res Treat, 42, 173-81.
  26. Krajewski S, Krajewska M, Turner BC, et al (1999). Prognostic significance of apoptosis regulators in breast cancer, Endocr Relat Cancer, 6, 29-40.
  27. Linjawi A, Kontogiannea M, Halwani F, Edwardes M, Meterissian S (2004). Prognostic significance of p53, bcl-2, and Bax expression in early breast cancer. J Am Coll Surg, 198, 83-90.
  28. Lipponen P (1999). Apoptosis in breast cancer: relationship with other pathological parameters. Endocrine Related Cancer, 6, 13-6.
  29. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, et al (1997). Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science, 277, 55-60.
  30. Merja V, Kimmo L, Hannu R, Paavo P, Yiermi S (1999). Apoptosis during breast carcinoma progression. Clin Cancer Res, 5, 319-24.
  31. Nazan G, Zafer A, Ugur C, et al (2002). Prognostic importance of tumor angiogenesis in breast carcinoma with adjuvant chemotherapy. Pathol Res Pract, 198, 7-12.
  32. Perrone G, Vincenzi B, Santini D, et al (2004). Correlation of 53 and bcl-2 expresion with vascular endothelial growth factor (VEGF), microvessel density (MVD) and clinicopathological features in colon cancer. Cancer Letters, 208, 227-34.
  33. Qureshi A, Pervez S (2010).Allred scoring for ER reporting and its impact in clearly distinguishing ER negative from ER positive breast cancers. J Pak Med Assoc, 60, 350-3.
  34. Ray SK, Patel SJ, Welsh CT, et al (2002). Molecular evidence of apoptotic death in malignant brain tumors including glioblastoma multiforme: upregulation of calpain and caspase-3. J Neurosci Res, 69, 197-206.
  35. Rochaix P, Krajewski S, Reed JC, et al (1999). In vivo patterns of Bcl-2 family protein expression in breast carcinoma in relation to apoptosis, J Pathol, 187, 410-5.
  36. Sirvent JJ, Aguilar MC, Olona M, et al (2004). Prognostic value of apoptosis in breast cancer (pT1-pT2). A TUNEL, p53, bcl-2, bag-1 and Bax immunohistochemical study. Histol Histopathol, 19, 759-70.
  37. Soini Y, Paakko P, Lehto VP (1998). Histopathological evaluation of apoptosis in cancer. Am J Pathol, 153, 1041-53.
  38. Tenderenda M, Rutkowski P, Jesionek-Kupnicka D, Kubiak R (2001). Expression of CD34 in gastric cancer and is correlation with histology grade, stage, proliferation activity, p53 expression and apoptotic index. Pathol Oncol Res, 7 129-34.
  39. Thurston G, Suri C, Smith K, et al (1999). Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science, 286, 2511-4.
  40. Tjalma WA, Weyler JJ, Bogers JJ, et al (2001). The importance of biological factors (bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer. Eur J Obstetrics Gynaecol Reprod Biol, 97, 223-30.
  41. Vamesu S (2008). Angiogenesis and tumor histologic type in primary breast cancer patients: an analysis of 155 needle core biopsies. Rom J Morphol Embryol, 49, 181-8.
  42. Veronese S, Mauri FA, Caffo O, et al (1998). Bax immunohistochemical expression in breast carcinoma: a study with long term follow-up. Int J Cancer, 79, 13-8.<13::AID-IJC3>3.0.CO;2-Z
  43. Vogl G, Dietze O, Hauser-Kronberger C (2005). Angiogenic potential of ductal carcinoma in situ (DCIS) of human breast, Histopathology, 47, 617-24.
  44. Weidner N, Semple JP, Welch WR, Folkman J (1991). Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med, 324, 1-8.
  45. White E (1996). Life, death, and the pursuit of apoptosis. A review. Genes Dev, 10, 1-15.
  46. Yancopoulos GD, Davis S, Gale NW, et al (2000). Vascular specific growth factors and blood vessel formation. Nature, 407, 242-8.
  47. Yang X, Hao Y, Ding Z, Pater A, Tang SC (1999). Differential expression of antiapoptotic gene BAG-1 in human breast normal and cancer cell lines and tissues. Clin Cancer Res 5. 1816-22.
  48. Yu Q, Stamenkovic I (2001). Angiopoietin-2 is implicated in the regulation of tumor angiogenesis. Am J Pathol, 158, 563-70.
  49. Zheng L, Dengler TJ, Kluger MS, et al (2000). Cytoprotection of human umbilical vein endothelial cells against apoptosis and CTL-mediated lysis provided by caspase-resistant Bcl- 2 without alterations in growth or activation responses. J Immunol, 164, S4665-71.

Cited by

  1. Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells vol.12, pp.1, 2012,
  2. Protective Effects of [6]-Paradol on Histological Lesions and Immunohistochemical Gene Expression in DMBA Induced Hamster Buccal Pouch Carcinogenesis vol.14, pp.5, 2013,
  3. Emodin Inhibits Breast Cancer Cell Proliferation through the ERα-MAPK/Akt-Cyclin D1/Bcl-2 Signaling Pathway vol.15, pp.15, 2014,
  4. Rapamycin and PF4 Induce Apoptosis by Upregulating Bax and Down-Regulating Survivin in MNU-Induced Breast Cancer vol.15, pp.9, 2014,
  5. Expression of Bcl-2 in Primary and Recurrent Odontogenic Keratocysts in Comparison with Other Odontogenic Lesions vol.16, pp.15, 2015,
  6. Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells vol.16, pp.17, 2015,
  7. Expression of Cox-2 and Bcl-2 in Paget's Disease of the Breast vol.16, pp.3, 2015,
  8. Cytotoxic activity of novel palladium-based compounds on leukemia cell lines vol.26, pp.2, 2015,