Androgen receptor expression in relation to apoptosis and the expression of cell cycle related proteins in prostate cancer

  • Zahra Amirghofran
  • Ahmad Monabati
  • Naser Gholijani


The expression of several genes involved in the regulation of cell cycle and apoptosis may be regulated via the androgen receptor (AR) in the prostate. AR may have a role in the prognosis of prostatic carcinoma. The aim was to examine AR expression status and its relationship with markers of proliferation, apoptosis and cell cycle control in prostate cancer. Expression of AR, bcl-2, bax, Ki-67 and p53 was examined in paraffin-embedded tissues from 50 cases of prostate carcinoma by immunohistochemistry and evaluated using an index of staining. Detection of apoptotic cells was performed by TUNEL method. Correlation between AR expression and apoptosis, proliferation index, bcl-2, bax and p53 and also clinicopathological parameters including stage, pathological grade and Gleason score were determined. AR expression was observed in all cases with mean expression of 81%±15 and mean staining index of 141±65. No correlation was found between AR expression and apoptosis detected in patients. The mean AR staining index was 170±72 in bcl-2 positive tumors versus 120±53 in bcl-2 negative tumors showing a significant association between AR and bcl-2 expression (p=0.015). AR expression also showed a significant association with bcl-2/bax ratio (r=0.321, p=0.023) and Ki-67 proliferation staining index (r=0.396, p=0.004). Although a significant correlation between Ki-67 and p53 with differentiation status of the tumors was observed (p<0.004) no correlation was found with AR. AR expression showed no prognostic value regarding its correlation with stage and differentiation status of the prostate carcinoma. However, its significant correlation with Ki-67 and bcl-2 that are markers of cell survival suggest its contribution to tumor cell progression.


prostate carcinoma androgen receptor apoptosis p53 bcl-2 bax Ki-67 


  1. 1.
    Buttyan R, Shabsigh A, Perlman H, Colombel M. Regulation of Apoptosis in the Prostate Gland by Androgenic Steroids. Trends Endocrinol Metab 10:47–54, 1999PubMedCrossRefGoogle Scholar
  2. 2.
    Chang C, Saltzman A, Yeh S et al.: Androgen receptor: an overview. Crit Rev Eukaryot Gene Exp 5: 97–125, 1995Google Scholar
  3. 3.
    Eder IE, Culig Z, Putz T et al.: Molecular biology of the androgen receptor: from molecular understanding to the clinic. Eur Urol 40:241–51, 2001PubMedCrossRefGoogle Scholar
  4. 4.
    Klocker H, Culig Z, Eder IE et al: Mechanism of androgen receptor activation and possible implications for chemoprevention trials. Eur Urol 35: 413–419, 1999.PubMedCrossRefGoogle Scholar
  5. 5.
    Kyprianou N, Isaacs JT: Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology 122: 552–562, 1988PubMedCrossRefGoogle Scholar
  6. 6.
    Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol 20: 3001–3015, 2002PubMedCrossRefGoogle Scholar
  7. 7.
    Feng Z, Joos HJ, Vallan C et al: Apoptosis during castrationinduced regression of the prostate is Fos dependent. Oncogene 19: 17: 2593–600, 1998CrossRefGoogle Scholar
  8. 8.
    Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. J Urol 168: 9–12, 2002PubMedCrossRefGoogle Scholar
  9. 9.
    Culig Z, Klocker H, Bartsch G et al: Androgen receptors in prostate cancer. J Urol 170: 1363–1369 2003.PubMedCrossRefGoogle Scholar
  10. 10.
    Culig Z, Hobisch A, Erdel M et al: Studies on androgen receptor mutations and amplification in human prostatecancer. Methods Mol Med 81: 267–275, 2003PubMedGoogle Scholar
  11. 11.
    Sadi MV, Barrack ER: Image analysis of androgen receptor immunostaining in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy. Cancer 15: 71: 2574–2580, 1993CrossRefGoogle Scholar
  12. 12.
    Miyamoto KK, McSherry SA, Dent GA et al.: Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue. J Urol 149:1015–1019, 1993PubMedGoogle Scholar
  13. 13.
    de Winter JA, Trapman J, Brinkmann AO et al: Androgen receptor heterogeneity in human prostatic carcinomas visualized by immunohistochemistry. J Pathol 160: 329–332, 1990PubMedCrossRefGoogle Scholar
  14. 14.
    Shaffer DR, Scher HI. Prostate cancer: a dynamic illness with shifting targets. Lancet Oncol 4: 407–414, 2003PubMedCrossRefGoogle Scholar
  15. 15.
    Magi-Galluzzi C, Xu X, Hlatky L et al: Heterogeneity of androgen receptor content in advanced prostate cancer. Mod Pathol 10: 839–845, 1997PubMedGoogle Scholar
  16. 16.
    Sweat SD, Pacelli A, Bergstralh EJ et al: Androgen receptor expression in prostatic intraepithelial neoplasia and cancer. J Urol 161: 1229–1232, 1999PubMedCrossRefGoogle Scholar
  17. 17.
    Yoshikawa H, Ikeuchi T, Kai Y. Immunohistochemical study of androgen receptor in adenocarcinoma of the human prostatic cancer. Nippon Hinyokika Gakkai Zasshi 87: 956–963, 1996PubMedGoogle Scholar
  18. 18.
    van der Kwast TH, Schalken J, Ruizeveld de Winter JA et al: Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 48: 189–193, 1991PubMedCrossRefGoogle Scholar
  19. 19.
    Takeda H, Akakura K, Masai M et al.: Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer 77: 934–940, 1996PubMedCrossRefGoogle Scholar
  20. 20.
    Finnegan NM, Curtin JF, Prevost G et al: Induction of apoptosis in prostate carcinoma cells by BH3 peptides which inhibit Bak/Bcl-2 interactions. Br J Cancer 85: 115–121, 2001PubMedCrossRefGoogle Scholar
  21. 21.
    DiPaola RS, Aisner J. Overcoming bcl-2- and p53-mediated resistance in prostate cancer. Semin Oncol 26(Suppl) 2: 112–116, 1999PubMedGoogle Scholar
  22. 22.
    Kolar Z, Murray PG, Madarova J et al: Nuclear receptors in early hormone refractory prostate cancer and their relationship to apoptosis-related proteins. Neoplasma 49:172–177, 2002PubMedGoogle Scholar
  23. 23.
    Fizazi K, Martinez LA, Sikes CR et al: The association of p21 (WAF-1/CIP1) with progression to androgen-independent prostate cancer. Clin Cancer Res 8: 775–781, 2002PubMedGoogle Scholar
  24. 24.
    Tanji N. Yokoyama M. Sagamoto T et al: Apoptosis in prostatic adenocarcinoma; A study of relationship to Ki-67 and bcl-2 protein expression. Anticancer Res 18:1111–1116, 1998PubMedGoogle Scholar
  25. 25.
    Kaltz-Wittmer C, Klenk U, Glaessgen A et al: FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy. Lab Invest 80: 1455–1464, 2000PubMedGoogle Scholar
  26. 26.
    Baretton GB, Klenk U, Diebold J et al: Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression. Br J Cancer 80: 546–555, 1999PubMedCrossRefGoogle Scholar
  27. 27.
    Cadwell C, Zambetti GP: The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth. Gene 17: 15–30, 2001CrossRefGoogle Scholar
  28. 28.
    Brooks JD, Bova GS, Ewing CM et al: An uncertain role for p53 gene alterations in human prostate cancers. Cancer Res 56: 3814–3822. 1996PubMedGoogle Scholar
  29. 29.
    Navone NM, Troncoso P, Pisters LL, et al.: p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst 85: 1657–1669, 1993PubMedCrossRefGoogle Scholar
  30. 30.
    Aprikian AG, Sarkis AS, Fair WR et al: Immunohistochemical determination of p53 protein nuclear accumulation in prostatic adenocarcinoma. J Urol 151: 1276–1280, 1994PubMedGoogle Scholar
  31. 31.
    Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol 14: 86–91, 2002PubMedCrossRefGoogle Scholar
  32. 32.
    Howell SB. Resistance to apoptosis in prostate cancer cells. Mol Urol 4: 225–229, 2000PubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2004

Authors and Affiliations

  • Zahra Amirghofran
    • 2
  • Ahmad Monabati
    • 1
    • 2
  • Naser Gholijani
    • 2
  1. 1.Department of Immunology, Medical SchoolShiraz University of Medical ScienceShirazIran
  2. 2.Department of Pathology, Medical SchoolShiraz University of Medical SciencesShirazIran

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