Tissue Levels of Androgens in Castration-Recurrent Prostate Cancer

  • James L. Mohler
  • Mark A. Titus


AR remains active in growth signaling despite castrate levels of circulating androgens. AR protein and AR-regulated proteins are expressed in CaP that recurs during ADT in both the primary and bone metastases. AR activation in recurrent CaP may occur by a variety of mechanisms that alter the sensitivity or specificity of AR. Recent studies using androgen-independent CaP cell lines and xenografts demonstrated that AR over-expression allowed recurrent CaP growth in the presence of castrate levels of circulating androgens. However, AR mutations that prevented ligand-binding prevented recurrent growth; over-expressed AR required ligand to confer recurrent growth. We showed that DHT levels were decreased by 91% in clinical specimens of castration-recurrent CaP (1.25 pmol/gm tissue) compared to androgen-stimulated benign prostate and DHT levels were sufficient for AR activation in most specimens of recurrent CaP. Other investigators have supported these findings in prostatectomy specimens obtained after 3-6 months of ADT and benign prostate specimens after 1 month of ADT. Perturbations in androgen metabolism pathways during ADT may allow intracrine production of DHT from adrenal androgens and even cholesterol. The tissue levels of T and DHT support a new paradigm. CaP that recurs after medical or surgical castration is not “androgen-independent” because recurrent CaP usually has androgen levels sufficient to activate AR. New treatments should be directed at preventing intracrine synthesis of testicular androgens from adrenal androgens or cholesterol, degrading these androgens or, failing both, destroying AR.


Prostate Cancer Androgen Receptor Androgen Deprivation Therapy Androgen Receptor Expression Adrenal Androgen 
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  1. Bartsch, W., Klein, H., Schiemann, U., Bauer, H. W., & Voigt, K. D. (1990). Enzymes of androgen formation and degradation in the human prostate. Ann N Y Acad Sci, 595, 53–66.PubMedCrossRefGoogle Scholar
  2. Bauman, D. R., Steckelbroeck, S., Williams, M. V., Peehl, D. M., & Penning, T. M. (2006). Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease. Mol Endocrinol, 20(2), 444–458.PubMedCrossRefGoogle Scholar
  3. Belanger, B., Belanger, A., Labrie, F., Dupont, A., Cusan, L., & Monfette, G. (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(5), 695–698.PubMedCrossRefGoogle Scholar
  4. Brown, R. S., Edwards, J., Dogan, A., Payne, H., Harland, S. J., Bartlett, J. M., et al. (2002). Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. J Pathol, 198(2), 237–244.PubMedCrossRefGoogle Scholar
  5. Catalona, W. J., Smith, D. S., Ratliff, T. L., Dodds, K. M., Coplen, D. E., Yuan, J. J., et al. (1991). Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med, 324(17), 1156–1161.PubMedCrossRefGoogle Scholar
  6. Culig, Z., Hoffmann, J., Erdel, M., Eder, I. E., Hobisch, A., Hittmair, A., 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(2), 242–251.PubMedCrossRefGoogle Scholar
  7. de Vere White, R., Meyers, F., Chi, S. G., Chamberlain, S., Siders, D., Lee, F., et al. (1997). Human androgen receptor expression in prostate cancer following androgen ablation. Eur Urol, 31(1), 1–6.PubMedGoogle Scholar
  8. Edwards, J., Krishna, N. S., Grigor, K. M., & Bartlett, J. M. (2003). Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer, 89(3), 552–556.PubMedCrossRefGoogle Scholar
  9. Eisenberger, M. A., Blumenstein, B. A., Crawford, E. D., Miller, G., McLeod, D. G., Loehrer, P. J., et al. (1998). Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med, 339(15), 1036–1042.PubMedCrossRefGoogle Scholar
  10. Feldman, B. J., & Feldman, D. (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer, 1(1), 34–45.PubMedCrossRefGoogle Scholar
  11. Ford, O. H., 3rd, Gregory, C. W., Kim, D., Smitherman, A. B., & Mohler, J. L. (2003). Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol, 170(5), 1817–1821.PubMedCrossRefGoogle Scholar
  12. Freeman, M. R., & Solomon, K. R. (2004). Cholesterol and prostate cancer. J Cell Biochem, 91(1), 54–69.PubMedCrossRefGoogle Scholar
  13. Geller, J., Albert, J., Loza, D., Geller, S., Stoeltzing, W., & de la Vega, D. (1978). DHT concentrations in human prostate cancer tissue. J Clin Endocrinol Metab, 46(3), 440–444.PubMedCrossRefGoogle Scholar
  14. 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(1B), 631–636.PubMedCrossRefGoogle Scholar
  15. Gelmann, E. P. (2002). Molecular biology of the androgen receptor. J Clin Oncol, 20(13), 3001–3015.PubMedCrossRefGoogle Scholar
  16. Gregory, C. W., Hamil, K. G., Kim, D., Hall, S. H., Pretlow, T. G., Mohler, J. L., et al. (1998). Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Res, 58(24), 5718–5724.PubMedGoogle Scholar
  17. Gregory, C. W., Kim, D., Ye, P., D'Ercole, A. J., Pretlow, T. G., Mohler, J. L., et al. (1999). Androgen receptor up-regulates insulin-like growth factor binding protein-5 (IGFBP-5) expression in a human prostate cancer xenograft. Endocrinology, 140(5), 2372–2381.PubMedCrossRefGoogle Scholar
  18. Gregory, C. W., He, B., Johnson, R. T., Ford, O. H., Mohler, J. L., French, F. S., et al. (2001a). A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res, 61(11), 4315–4319.Google Scholar
  19. Gregory, C. W., Johnson, R. T., Jr., Mohler, J. L., French, F. S., & Wilson, E. M. (2001b). Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res, 61(7), 2892–2898.Google Scholar
  20. Gregory, C. W., Johnson, R. T., Jr., Presnell, S. C., Mohler, J. L., & French, F. S. (2001c). Androgen receptor regulation of G1 cyclin and cyclin-dependent kinase function in the CWR22 human prostate cancer xenograft. J Androl, 22(4), 537–548.Google Scholar
  21. Grossmann, M. E., Huang, H., & Tindall, D. J. (2001). Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst, 93(22), 1687–1697.PubMedCrossRefGoogle Scholar
  22. Guo, Z., Dai, B., Jiang, T., Xu, K., Xie, Y., Kim, O., et al. (2006). Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell, 10(4), 309–319.PubMedCrossRefGoogle Scholar
  23. Harper, M. E., Pike, A., Peeling, W. B., & Griffiths, K. (1974). Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol, 60(1), 117–125.PubMedCrossRefGoogle Scholar
  24. Hobisch, A., Culig, Z., Radmayr, C., Bartsch, G., Klocker, H., & Hittmair, A. (1995). Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res, 55(14), 3068–3072.PubMedGoogle Scholar
  25. Hsing, A. W., Reichardt, J. K., & Stanczyk, F. Z. (2002). Hormones and prostate cancer: current perspectives and future directions. Prostate, 52(3), 213–235.PubMedCrossRefGoogle Scholar
  26. Huggins, C., & Hodges, C. V. (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(1), 9–12.PubMedCrossRefGoogle Scholar
  27. Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., & Thun, M. J. (2007). Cancer statistics, 2007. CA Cancer J Clin, 57(1), 43–66.PubMedCrossRefGoogle Scholar
  28. Labrie, F., Dupont, A., Belanger, A., Cusan, L., Lacourciere, Y., Monfette, G., et al. (1982). New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med, 5(4), 267–275.PubMedGoogle Scholar
  29. Linja, M. J., Savinainen, K. J., Saramaki, O. R., Tammela, T. L., Vessella, R. L., & Visakorpi, T. (2001). Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res, 61(9), 3550–3555.PubMedGoogle Scholar
  30. Mahajan, N. P., Liu, Y., Majumder, S., Warren, M. R., Parker, C. E., Mohler, J. L., et al. (2007). Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A, 104(20), 8438–8443.PubMedCrossRefGoogle Scholar
  31. Prostate Cancer Trialists' Collaborative Group (1995). Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet, 346(8970), 265–269.Google Scholar
  32. Miyake, H., Pollak, M., & Gleave, M. E. (2000). Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. Cancer Res, 60(11), 3058–3064.PubMedGoogle Scholar
  33. Mizokami, A., Koh, E., Fujita, H., Maeda, Y., Egawa, M., Koshida, K., 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(2), 765–771.PubMedCrossRefGoogle Scholar
  34. Mohler, J. L., Morris, T. L., Ford, O. H., 3rd, Alvey, R. F., Sakamoto, C., & Gregory, C. W. (2002). Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer. Prostate, 51(4), 247–255.PubMedCrossRefGoogle Scholar
  35. Mohler, J. L., Gregory, C. W., Ford, O. H., 3rd, Kim, D., Weaver, C. M., Petrusz, P., et al. (2004). The androgen axis in recurrent prostate cancer. Clin Cancer Res, 10(2), 440–448.PubMedCrossRefGoogle Scholar
  36. Mohler, J. L., Titus, M., Lih, F., & Tomer, K. (2007). Method for determination of DHT levels in tissue samples.Google Scholar
  37. Mousses, S., Wagner, U., Chen, Y., Kim, J. W., Bubendorf, L., Bittner, M., et al. (2001). Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene, 20(46), 6718–6723.PubMedCrossRefGoogle Scholar
  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(21), 7121–7126.PubMedCrossRefGoogle Scholar
  39. Page, S. T., Lin, D. W., Mostaghel, E. A., Hess, D. L., True, L. D., Amory, J. K., et al. (2006). Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab.Google Scholar
  40. Penning, T. M., Steckelbroeck, S., Bauman, D. R., Miller, M. W., Jin, Y., Peehl, D. M., et al. (2006). Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol, 248(1–2), 182–191.PubMedCrossRefGoogle Scholar
  41. Sadar, M. D., Hussain, M., & Bruchovsky, N. (1999). Prostate cancer: molecular biology of early progression to androgen independence. Endocr Relat Cancer, 6(4), 487–502.PubMedCrossRefGoogle Scholar
  42. Schaffner, C. P. (1981). Prostatic cholesterol metabolism: regulation and alteration. Prog Clin Biol Res, 75A, 279–324.PubMedGoogle Scholar
  43. Simard, J., Luthy, I., Guay, J., Belanger, A., & Labrie, F. (1986). Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol, 44(3), 261–270.PubMedCrossRefGoogle Scholar
  44. Stanbrough, M., Bubley, G. J., Ross, K., Golub, T. R., Rubin, M. A., Penning, T. M., et al. (2006). Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res, 66(5), 2815–2825.PubMedCrossRefGoogle Scholar
  45. Stege, R., Tribukait, B., Lundh, B., Carlstrom, K., Pousette, A., & Hasenson, M. (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(3), 833–837.PubMedGoogle Scholar
  46. Stewart, R. J., Panigrahy, D., Flynn, E., & Folkman, J. (2001). Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol, 165(2), 688–693.PubMedCrossRefGoogle Scholar
  47. Taplin, M. E., Bubley, G. J., Shuster, T. D., Frantz, M. E., Spooner, A. E., Ogata, G. K., et al. (1995). Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med, 332(21), 1393–1398.PubMedCrossRefGoogle Scholar
  48. Taplin, M. E., Bubley, G. J., Ko, Y. J., Small, E. J., Upton, M., Rajeshkumar, B., et al. (1999). Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res, 59 (11), 2511–2515.PubMedGoogle Scholar
  49. Titus, M. A., Gregory, C. W., Ford, O. H., 3rd, Schell, M. J., Maygarden, S. J., & Mohler, J. L. (2005a). Steroid 5alpha-reductase isozymes I and II in recurrent prostate cancer. Clin Cancer Res, 11(12), 4365–4371.CrossRefGoogle Scholar
  50. Titus, M. A., Schell, M. J., Lih, F. B., Tomer, K. B., & Mohler, J. L. (2005b). Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res, 11(13), 4653–4657.CrossRefGoogle Scholar
  51. van der Kwast, T. H., Schalken, J., Ruizeveld de Winter, J. A., van Vroonhoven, C. C., Mulder, E., Boersma, W., et al. (1991). Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer, 48(2), 189–193.PubMedCrossRefGoogle Scholar
  52. Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., et al. (1995). In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet, 9(4), 401–406.PubMedCrossRefGoogle Scholar
  53. Yang, Y., Chisholm, G. D., & Habib, F. K. (1992). The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate. Prostate, 21(3), 201–208.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Urologic Oncology, Roswell Park Cancer InstituteBuffaloUSA

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