Castration-Recurrent Prostate Cancer Is Not Androgen-Independent

  • James L. Mohler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

In the USA in 2006, an estimated 234,460 new cases of prostate cancer (PC) will be diagnosed and 27,350 men will die from PC (1). Despite the increased use of digital rectal examination and serum prostate-specific antigen (PSA) measurement for early detection, ∼30% of men treated with curative intent suffer PC recurrence. These men and those who present with locally advanced or metastatic PC can be palliated by androgen deprivation therapy (ADT), a treatment that remains unimproved since its discovery more than 60 years ago (2). Over 80% of men with disseminated PC demonstrate clinical or biochemical response that is associated with a mean life expectancy of ∼3.5 years in contrast to nonresponders or untreated patients who live an average of 9 months. Regardless of the androgen responsiveness of incurable PC, almost all patients succumb to castration-recurrent PC because it responds poorly to all known therapies.


Prostate Cancer Androgen Receptor Androgen Deprivation Therapy Androgen Receptor Gene Adrenal Androgen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemal A, Siegel R, Ward E, et al. (2006) Cancer statistics, 2006. CA Cancer J Clin 56: 106–130.PubMedCrossRefGoogle Scholar
  2. 2.
    Huggins C, Hodges CV (2002) Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 168: 9–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Mohler JL, Gregory CW, Ford OH III, et al. (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10: 440–448.PubMedCrossRefGoogle Scholar
  4. 4.
    van der Kwast TH, Schalken J, Ruizeveld de Winter JA, et al. (1991) Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 48: 189–193.PubMedCrossRefGoogle Scholar
  5. 5.
    Visakorpi T, Hyytinen E, Koivisto P, et al. (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9: 401–406.PubMedCrossRefGoogle Scholar
  6. 6.
    Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Gelmann EP (2002) Molecular biology of the androgen receptor. J Clin Oncol 20: 3001–3015.PubMedCrossRefGoogle Scholar
  8. 8.
    Grossmann ME, Huang H, Tindall DJ (2001) Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 93: 1687–1697.PubMedCrossRefGoogle Scholar
  9. 9.
    Sadar MD, Hussain M, Bruchovsky N (1999) Prostate cancer: molecular biology of early progression to androgen independence. Endocr Relat Cancer 6: 487–502.PubMedCrossRefGoogle Scholar
  10. 10.
    Takahashi H, Furusato M, Allsbrook WC, Jr, et al. (1995) Prevalence of androgen receptor gene mutations in latent prostatic carcinomas from Japanese men. Cancer Res 55: 1621–1624.PubMedGoogle Scholar
  11. 11.
    Tilley WD, Buchanan G, Hickey TE, et al. (1996) Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res 2: 277–285.PubMedGoogle Scholar
  12. 12.
    Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, et al. (1994) Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol 144: 735–746.PubMedGoogle Scholar
  13. 13.
    Taplin ME, Bubley GJ, Shuster TD, et al. (1995) Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332: 1393–1398.PubMedCrossRefGoogle Scholar
  14. 14.
    Greene SL, Stockton P, Kozyreva OG, et al. (2003) Mutational analysis of the androgen receptor using laser capture microdissection and direct sequencing. In: Terrain D (ed.) Cancer Cell Signalling: Methods and Protocols. Humana Press, Totowa, NJ, pp. 287–302.Google Scholar
  15. 15.
    Taplin ME, Bubley GJ, Ko YJ, et al. (1999) Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59: 2511–2515.PubMedGoogle Scholar
  16. 16.
    Shi XB, Ma AH, Xia L, et al. (2002) Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 62: 1496–1502.PubMedGoogle Scholar
  17. 17.
    Culig Z, Hobisch A, Cronauer MV, et al. (1993) Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol 7: 1541–1550.PubMedCrossRefGoogle Scholar
  18. 18.
    Peterziel H, Culig Z, Stober J, et al. (1995) Mutant androgen receptors in prostatic tumors distinguish between amino-acid-sequence requirements for transactivation and ligand binding. Int J Cancer 63: 544–550.PubMedCrossRefGoogle Scholar
  19. 19.
    Tan J, Sharief Y, Hamil KG, et al. (1997) Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 11: 450–459.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen CD, Welsbie DS, Tran C, et al. (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Ford OH, 3rd, Gregory CW, Kim D, et al. (2003) Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol 170: 1817–1821.PubMedCrossRefGoogle Scholar
  22. 22.
    Palmberg C, Koivisto P, Kakkola L, et al. (2000) Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol 164: 1992–1995.PubMedCrossRefGoogle Scholar
  23. 23.
    Ueda T, Bruchovsky N, Sadar MD (2002) Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem 277: 7076–7085.PubMedCrossRefGoogle Scholar
  24. 24.
    Ueda T, Mawji NR, Bruchovsky N, et al. (2002) Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem 277: 38087–38094.PubMedCrossRefGoogle Scholar
  25. 25.
    Yeh S, Lin HK, Kang HY, et al. (1999) From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA 96: 5458–5463.PubMedCrossRefGoogle Scholar
  26. 26.
    Liu Y, Majumder S, McCall W, et al. (2005) Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res 65: 3404–3409.PubMedGoogle Scholar
  27. 27.
    Mahajan NP, Whang YE, Mohler JL, et al. (2005) Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. Cancer Res 65: 10514–10523.PubMedCrossRefGoogle Scholar
  28. 28.
    Park SY, Kim YJ, Gao AC, et al. (2006) Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res 66: 5121–5129.PubMedCrossRefGoogle Scholar
  29. 29.
    Smitherman AB, Gregory CW, Mohler JL (2003) Apoptosis levels increase after castration in the CWR22 human prostate cancer xenograft. Prostate 57: 24–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Dai J, Shen R, Sumitomo M, et al. (2002) Synergistic activation of the androgen receptor by bombesin and low-dose androgen. Clin Cancer Res 8: 2399–2405.PubMedGoogle Scholar
  31. 31.
    Titus MA, Schell MJ, Lih FB, et al. (2005) Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 11: 4653–4657.PubMedCrossRefGoogle Scholar
  32. 32.
    Belanger B, Belanger A, Labrie F, et al. (1989) Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men. J Steroid Biochem 32: 695–698.PubMedCrossRefGoogle Scholar
  33. 33.
    Labrie F, Dupont A, Belanger A, et al. (1982) New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med 5: 267–275.PubMedGoogle Scholar
  34. 34.
    Prostate Cancer Trialists’ Collaborative Group (1995) Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet 265–269.Google Scholar
  35. 35.
    Eisenberger MA, Blumenstein BA, Crawford ED, et al. (1998) Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036–1042.PubMedCrossRefGoogle Scholar
  36. 36.
    Geller J, Albert J, Loza D (1979) Steroid levels in cancer of the prostate –markers of tumour differentiation and adequacy of anti-androgen therapy. J Steroid Biochem 11: 631–636.PubMedCrossRefGoogle Scholar
  37. 37.
    Mizokami A, Koh E, Fujita H, et al. (2004) The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res 64: 765–771.PubMedCrossRefGoogle Scholar
  38. 38.
    Nishiyama T, Hashimoto Y, Takahashi K (2004) The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin Cancer Res 10: 7121–7126.PubMedCrossRefGoogle Scholar
  39. 39.
    Page ST, Lin DW, Mostaghel EA, et al. (2006) Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy Men. J Clin Endocrinol Metab 91: 3850–3856.PubMedCrossRefGoogle Scholar
  40. 40.
    Simard J, Luthy I, Guay J, et al. (1986) Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol 44: 261–270.PubMedCrossRefGoogle Scholar
  41. 41.
    Gregory CW, Johnson RT, Jr, Mohler JL, et al. (2001) Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 61: 2892–2898.PubMedGoogle Scholar
  42. 42.
    Culig Z, Hoffmann J, Erdel M, et al. (1999) Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 81: 242–251.PubMedCrossRefGoogle Scholar
  43. 43.
    Stege R, Tribukait B, Lundh B, et al. (1992) Quantitative estimation of tissue prostate specific antigen, deoxyribonucleic acid ploidy and cytological grade in fine needle aspiration biopsies for prognosis of hormonally treated prostatic carcinoma. J Urol 148: 833–837.PubMedGoogle Scholar
  44. 44.
    Yang Y, Chisholm GD, Habib FK (1992) The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate. Prostate 21: 201–208.PubMedCrossRefGoogle Scholar
  45. 45.
    Bartsch W, Klein H, Schiemann U, et al. (1990) Enzymes of androgen formation and degradation in the human prostate. Ann N Y Acad Sci 595: 53–66.PubMedCrossRefGoogle Scholar
  46. 46.
    Gregory CW, He B, Johnson RT, et al. (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61: 4315–4319.PubMedGoogle Scholar
  47. 47.
    Harper ME, Pike A, Peeling WB, et al. (1974) Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol 60: 117–125.PubMedCrossRefGoogle Scholar
  48. 48.
    Kim D, Gregory CW, French FS, et al. (2002) Androgen receptor expression and cellular proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 prostate cancer xenograft. Am J Pathol 160: 219–226.PubMedGoogle Scholar
  49. 49.
    Taplin ME, Balk SP (2004) Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem 91: 483–490.PubMedCrossRefGoogle Scholar
  50. 50.
    Edwards J, Krishna NS, Grigor KM, et al. (2003) Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89: 552–556.PubMedCrossRefGoogle Scholar
  51. 51.
    Linja MJ, Savinainen KJ, Saramaki OR, et al. (2001) Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61: 3550–3555.PubMedGoogle Scholar
  52. 52.
    Brown RS, Edwards J, Dogan A, et al. (2002) Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. J Pathol 198: 237–244.PubMedCrossRefGoogle Scholar
  53. 53.
    Hobisch A, Culig Z, Radmayr C, et al. (1995) Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res 55: 3068–3072.PubMedGoogle Scholar
  54. 54.
    Hsing AW, Reichardt JK, Stanczyk FZ (2002) Hormones and prostate cancer: current perspectives and future directions. Prostate 52: 213–235.PubMedCrossRefGoogle Scholar
  55. 55.
    Stanbrough M, Bubley GJ, Ross K, et al. (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66: 2815–2825.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • James L. Mohler
    • 1
  1. 1.Urologic Oncology University of North CarolinaChapel HillUSA

Personalised recommendations