Clinical and Translational Oncology

, Volume 11, Issue 1, pp 5–10

Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway

  • Begoña Mellado
  • Jordi Codony
  • María José Ribal
  • Laura Visa
  • Pere Gascón
Educational Series Molecular and Cellular Biology of Cancer


Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are a number of novel agents targeting the AR signalling pathway under development, including more effective antiandrogens; inhibitors of CYP17, inhibitors of HSP90, inhibitors of histone deacetylases and inhibitors of tyrosine kinase inhibitors.


Prostate cancer Androgen-independence Androgen receptor 


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  1. 1.
    Feldman BF, Feldman D (2001) The development of androgen-independent prostate cancer. Nature Rev 1:34–45CrossRefGoogle Scholar
  2. 2.
    Debes JD, Tindall DJ (2004) Mechanisms of androgen-refractory prostate cancer. N Engl J Med 351:1488–1490PubMedCrossRefGoogle Scholar
  3. 3.
    Scher HI, Sawyers CL (2003) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor axis. J Clin Oncol 23:8253–8261CrossRefGoogle Scholar
  4. 4.
    Chen Yu, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8:440–448PubMedCrossRefGoogle Scholar
  5. 5.
    Taplin ME (2008) Androgen receptor: role and novel therapeutic prospects in prostate cancer. Exp Rev Anticancer Ther 8:1495–1508. ReviewCrossRefGoogle Scholar
  6. 6.
    Mohler JL (2008) Castration-recurrent prostate cancer is not androgen-independent. Adv Exp Med Biol 617:223–234. ReviewPubMedCrossRefGoogle Scholar
  7. 7.
    Agoulnik IU, Weigel NL (2008) Androgen receptor coactivators and prostate cancer. Adv Exp Med Biol 617:245–255. ReviewPubMedCrossRefGoogle Scholar
  8. 8.
    Centenera MM, Harris JM, Tilley WD, Butler LM (2008) The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol 22:2373–2382. ReviewPubMedCrossRefGoogle Scholar
  9. 9.
    Hsieh AC, Small EJ, Ryan CJ (2007) Androgenresponse elements in hormone-refractory prostate cancer: implications for treatment development. Lancet Oncol 8:933–939. ReviewPubMedCrossRefGoogle Scholar
  10. 10.
    Heemers HV, Tindall DJ (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28:778–808. ReviewPubMedCrossRefGoogle Scholar
  11. 11.
    Wang Y, Kreisberg JI, Ghosh PM (2007) Crosstalk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. Curr Cancer Drug Targets 7:591–604. ReviewPubMedCrossRefGoogle Scholar
  12. 12.
    Tomlins SA, Laxman B, Varambally S et al (2008) Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 10:177–188PubMedCrossRefGoogle Scholar
  13. 13.
    Ratliff TL (2005) Mutation of the androgen receptor causes oncogenic transformation of the prostate. J Urol 174:1149Google Scholar
  14. 14.
    Hara T, Miyazaki J, Araki H et al (2003) Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 63:149–153PubMedGoogle Scholar
  15. 15.
    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 231:1393–1398CrossRefGoogle Scholar
  16. 16.
    Ozers MS, Marks BD, Gowda K et al (2007) The androgen receptor T877A mutant recruits LXXLL and FXXLF peptides differently than wild-type androgen receptor in a time-resolved fluorescence resonance energy transfer assay. Biochemistry 46: 683–695PubMedCrossRefGoogle Scholar
  17. 17.
    Monge A, Jagla M, Lapouge G et al (2006) Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer. Cell Mol Life Sci 63:487–497PubMedCrossRefGoogle Scholar
  18. 18.
    Marques RB, Erkens-Schulze S, de Ridder CM et al (2005) Androgen receptor modifications in prostate cancer cells upon long-term androgen ablation and antiandrogen treatment. Int J Cancer 117:221–229PubMedCrossRefGoogle Scholar
  19. 19.
    Taplin ME, Rajeshkumar B, Halabi S et al (2003) Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol 21:2673–2678PubMedCrossRefGoogle Scholar
  20. 20.
    Bergerat JP, Céraline J (2008) Pleiotropic functional properties of androgen receptor mutants in prostate cancer. Hum Mutat Sept 17. [Epub ahead of print]Google Scholar
  21. 21.
    Tomillero A, Moral MA (2008) Gateways to clinical trials. Methods Find Exp Clin Pharmacol 30: 383–408PubMedGoogle Scholar
  22. 22.
    Holzbeierlein J, Lal P, LaTulippe E et al (2004) Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen- responsive genes and mechanisms of therapy resistance. Am J Pathol 164:217–227PubMedGoogle Scholar
  23. 23.
    Chen CD, Welsbie DS, Tran C et al (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33–39PubMedCrossRefGoogle Scholar
  24. 24.
    Titus MA, Schell MJ, Lih FB et al (2005) Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 11:4653–4657PubMedCrossRefGoogle Scholar
  25. 25.
    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 66:2815–2825PubMedCrossRefGoogle Scholar
  26. 26.
    Thomas LN, Douglas RC, Lazier CB et al (2008) Type 1 and type 2 5alpha-reductase expression in the development and progression of prostate cancer. Eur Urol 53:244–252PubMedCrossRefGoogle Scholar
  27. 27.
    Montgomery RB, Mostaghel EA, Vessella R et al (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447–4454PubMedCrossRefGoogle Scholar
  28. 28.
    Reid AH, Attard G, Barrie E, de Bono JS (2008) CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 5:610–620PubMedCrossRefGoogle Scholar
  29. 29.
    Attard G, Reid AH, Yap TA et al (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26:4563–4571PubMedCrossRefGoogle Scholar
  30. 30.
    Domingo-Domenech J, Fernandez PL, Filella X et al (2008) Serum HER2 extracellular domain predicts an aggressive clinical outcome and biological PSA response in hormone-independent prostate cancer patients treated with docetaxel. Ann Oncol 19:269–275PubMedCrossRefGoogle Scholar
  31. 31.
    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 65:3404–3409PubMedGoogle Scholar
  32. 32.
    Gregory CW, Whang YE, McCall W et al (2005) Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 11:1704–1712PubMedCrossRefGoogle Scholar
  33. 33.
    Whang YE, Moore CN, Armstrong AJ et al (2008) A phase II trial of lapatinib in hormone refractory prostate cancer. J Clin Oncol 26:16037 [Abstract]Google Scholar
  34. 34.
    Jin RJ, Lho Y, Connelly L et al (2008) The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Res 68:6762–6769PubMedCrossRefGoogle Scholar
  35. 35.
    Reddy GP, Barrack ER, Dou QP et al (2006) Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. Cell Biochem 98:1408–1423CrossRefGoogle Scholar
  36. 36.
    Malinowska K, Neuwirt H, Cavarretta I et al (2008) Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer Nov 14. [Epub ahead of print]Google Scholar
  37. 37.
    Seaton A, Scullin P, Maxwell PJ et al (2008) Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. Carcinogenesis29:1148–1156PubMedCrossRefGoogle Scholar
  38. 38.
    Robinson DR, Zylstra CR, Williams BO (2008) Wnt signaling and prostate cancer. Curr Drug Targets 9:571–580PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Y, Kreisberg JI, Ghosh PM (2007) Crosstalk between the androgen receptor and the phosphatidylinositol3-kinase/Akt pathway in prostate cancer. Cancer Drug Targets 7:591–604CrossRefGoogle Scholar
  40. 40.
    Solit DB, Scher HI, Rosen N (2003) Hsp90 as a therapeutic target in prostate cancer. Semin Oncol 30:709–716PubMedCrossRefGoogle Scholar
  41. 41.
    Sharifi N, Hurt EM, Farrar WL (2008) Androgen receptor expression in prostate cancer stem cells: is there a conundrum? Cancer Chemother Pharmacol 62:921–923PubMedCrossRefGoogle Scholar
  42. 42.
    Maitland NJ, Collins AT (2008) Prostate cancer stem cells: a new target for therapy. J Clin Oncol 26:2862–2870. ReviewPubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  • Begoña Mellado
    • 1
  • Jordi Codony
    • 1
  • María José Ribal
    • 2
  • Laura Visa
    • 1
  • Pere Gascón
    • 1
  1. 1.Medical Oncology Department, ICMHO Laboratory of Translational OncologyIDIBAPS, Hospital ClinicBarcelonaSpain
  2. 2.Urology DepartmentHospital ClinicBarcelonaSpain

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