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The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer

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Abstract

The androgen receptor (AR) is an androgen-inducible transcription factor characterized by a modular primary structure, with each module representing a distinct functional unit. After its interaction with androgens, the cytoplasmic AR is activated and translocated to the nucleus where it binds to target genes at the androgen responsive element(s) and recruits coregulators to form a multiprotein complex that interacts with transcriptional mediators and the basal transcription machinery to regulate gene transcription. Androgens play an essential role in the morphogenesis and physiology of the normal prostate. The etiology of benign prostatic hyperplasia lpar;BPH) and prostatic neoplasia, which can progress to adenocarcinoma, is androgen-dependent, and reduction/obliteration of androgen action in the prostate has been the therapy of choice for BPH and prostate cancer. After androgen withdrawal and antiandrogen treatment, the androgen responsive prostate cancer cells cease to proliferate and undergo apoptosis, causing tumor regression. However, relapses are seen invariably, when tumors emerge as androgen-independent and apoptosis-resistant. Gene amplification and amino acid substitutions in the AR are detected at a high frequency in recurrent tumors. These changes confer growth advantage to the tumor cells due to either hypersensitivity of AR to low, castrate-level androgens or a realignment of the receptor conformation, leading to altered ligand specificity that enables antiandrogens, adrenal androgens and non-androgen steroids act agonistically to increase AR activity. Persistence of signaling by the wild-type AR in therapy-resistant tumors is due to the increased receptor activity caused by cross talk of AR with multiple intracellular signaling cascades, especially the growth factor activated MAP kinase/ERK and PI3 kinase/Akt pathways. Ablation of AR function using antisense oligodeoxynucleotides, ribozymes or small interference RNAs (RNAi) holds promise as future approaches to the successful treatment of hormone-refractory, apoptosis-resistant prostate tumors.

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References

  1. Kokontis JM, Liao S: Molecular action of androgen in the normal and neoplastic prostate. Vitam Horm 55: 219-307, 1999

    Google Scholar 

  2. Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, Bi BY, Chatterjee B: Regulation of androgen action. Vitam Horm 55: 309-352, 1999

    Google Scholar 

  3. Heinlein CA, Chang C: Androgen receptor (AR) coregulators: An overview. Endocr Rev 23: 175-200, 2002

    Google Scholar 

  4. Gelman EP: Molecular biology of the androgen receptor. J Clin Oncol 20: 3001-3015, 2002

    Google Scholar 

  5. Culig Z, Klocker H, Bartsch G, Hobisch A: Androgen receptors in prostate cancer endocrine-related Cancer 9: 155-170, 2002

    Google Scholar 

  6. Balk SP: Androgen receptor as a target in androgen-independent prostate cancer. Urology 60: 132-138, 2002

    Google Scholar 

  7. Grossmann ME, Huang H, Tindall DJ: Androgen receptor signaling in androgen-refractory prostate cancer. J Nat Cancer Inst 93: 1687-1697, 2001

    Google Scholar 

  8. Griffin J: Androgen resistance: The clinical and molecular spectrum. N Engl J Med 326: 611-618, 1992

    Google Scholar 

  9. McNeal JE: The prostate gland: Morphology and pathobiology. Monogr Urol 4: 3-33, 1983

    Google Scholar 

  10. Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ, Sugimura Y: The endocrinology and developmental biology of the prostate. Endocr Rev 8: 338-362, 1987

    Google Scholar 

  11. Cunha GR: Growth factors as mediators of androgen action during male urogenital development. Prostate 6(suppl): 22-25, 1996

    Google Scholar 

  12. Isaacs JT, Coffey DS: Etiology and disease process of benign prostatic hyperplasia. Prostate 2(suppl): 33-50, 1989

    Google Scholar 

  13. De Marzo AM, Coffey DS, Nelson WG: New concepts in tissue specificity for prostate cancer and benign prostatic hyperplasia. Urology 53: 29-39, 1999

    Google Scholar 

  14. Hudson DL, Guy AT, Fry P, O'Hare MJ, Watt FM, Masters JR: Epithelial cell differentiation pathways in the human prostate: Identification of intermediate phenotypes by keratin expression. J Histochem Cytochem 49: 271-278, 2001

    Google Scholar 

  15. Tyagi RK, Lavrovsky Y, Ahn SC, Song CS, Chatterjee B, Roy AK: Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol Endocrinol 14: 1162-1174, 2000

    Google Scholar 

  16. Rachez C, Freedman LP: Mediator complexes and transcription. Curr Opin Cell Biol 13: 274-280, 2001

    Google Scholar 

  17. Wang Q, Sharma D, Ren Y, Fondell JD: A coregulatory role for the TRAP/Mediator complex in androgen receptor mediated gene expression. A coregulatory role for the TRAP/mediator complex in androgen receptor mediated gene expression. J Biol Chem 277: 42852-42858, 2002

    Google Scholar 

  18. McKenna NJ, O'Malley BW: Nuclear receptor coactivators — an update. Endocrinology 143: 2461-2465, 2002

    Google Scholar 

  19. Bevan CL, Hoare S, Claessens F, Heery DM, Parker MG: The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol 19: 8383-8392, 1999

    Google Scholar 

  20. Stallcup MR: Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20: 3014-3020, 2001

    Google Scholar 

  21. Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, Briggs SD, Allis CD, Wong J, Tempst P, Zhang Y: Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293: 853-857, 2001

    Google Scholar 

  22. Lu J, Danielsen M: Differential regulation of androgen and glucocorticoid receptors by retinoblastoma protein. J Biol Chem 273: 31528-31533, 1998

    Google Scholar 

  23. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn CS, Oh T, Chatterjee B: Androgen receptor: Structural domains and functional dynamics after ligand-receptor interactions. Ann NY Acad Sci 949: 44-57, 2001

    Google Scholar 

  24. Quigley CA, DeBillis A, Marschke KB, El-Awady MK, Wilson EM, French FS: Endocr Rev 16: 271-321, 1995

    Google Scholar 

  25. Faber PW, van Rooij HC, van der Korput HA, Baarends WM, Brinkmann AO, Grootegoed JA, Trapman J: Characterization of the human androgen receptor transcription unit. J Biol Chem 266: 10743-10749, 1991

    Google Scholar 

  26. Walcott JL, Merry DE: Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem 277: 50855-50859, 2002

    Google Scholar 

  27. Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, Sesterhenn IA, Mostofi FK, Benichou J, Chang: Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: A population-based case-control study in China. Cancer Res 60: 5111-5116, 2000

    Google Scholar 

  28. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH, Kantoff PW: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 94: 3320-3323, 1997

    Google Scholar 

  29. Ning YM, Robins DM: AML3/CBFalpha1 is required for androgen-specific activation of the enhancer of the mouse sex-limited protein (Slp) gene. J Biol Chem 274: 30624-30630, 1999

    Google Scholar 

  30. Robins DM, Robins DM, Scheller A, Adler AJ: Specific steroid response from a nonspecific DNA element. J Steroid Biochem Mol Biol 49: 251-255, 1994

    Google Scholar 

  31. Song CS, Jung MH, Kim SC, Hassan T, Roy AK, Chatterjee B: Tissue-specific and androgen repressible regulation of rat dehydroepiandrosterone sulfotransferase gene. J Biol Chem 273: 21856-21866, 1998

    Google Scholar 

  32. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Basler S, Schafer M, Egner U, Carrondo MA: Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic genene mutations. J Biol Chem 275: 26164-26171, 2000

    Google Scholar 

  33. Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE, Salvati ME, Krystek SR Jr, Weinmann R, Einspahr HM: Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA 98: 4904-4909, 2001

    Google Scholar 

  34. He B, Kemppainen JA, Voegel JJ, Gronemeyer H, Wilson EM: Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain. J Biol Chem 274: 37219-37225, 1999

    Google Scholar 

  35. Ikonen T, Palvimo JJ, Janne OA: Interaction between the amino-and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem 272: 29821-29828, 1997

    Google Scholar 

  36. Wang Qi, Lu JinHua, Yong EL: Ligand-and coactivator-mediated transactivation function (AF2) of the androgen receptor ligand-binding domain is inhibited by the cognate hinge region. J Biol Chem 276: 7493-7499, 2001

    Google Scholar 

  37. Wu CP, Gu FL: The prostate in eunuchs. Prog Clin Biol Res 370: 249-255, 1991

    Google Scholar 

  38. Bostwick DG: Prostatic intraepithelial neoplasia. Curr Urol Rep 1: 65-70, 2000

    Google Scholar 

  39. Craft N, Shostak Y, Carey M, Sawyers CL: A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5: 280-285, 1999

    Google Scholar 

  40. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, Wilson EM: A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61: 4315-4319, 2001

    Google Scholar 

  41. Pollard M, Luckert PH: The inhibitory effect of 4-hydroxyphenyl retinamide (4-HPR) on metastasis of prostate adenocarcinoma-III cells in Lobund-Wistar rats. Cancer Lett 59: 159-163, 1991

    Google Scholar 

  42. Peehl DM, Stamey TA: Serum-free growth of adult human prostatic epithelial cells. In Vitro Cell Dev Biol 2: 82-90, 1986

    Google Scholar 

  43. Knudsen KE, Arden KC, Cavenee WK: Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells. J Biol Chem 273: 20213-20222, 1998

    Google Scholar 

  44. Lu S, Tsai SY, Tsai MJ: Regulation of androgen-dependent prostatic cancer cell growth: Androgen regulation of CDK2, CDK4, CKI p16 genes. Cancer Res 57: 4511-4516, 1997

    Google Scholar 

  45. Yeh S, Miyamoto H, Nishimura K, Kang H, Ludlow J, Hsiao P, Wang C, Su C, Chang C: Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochem Biophys Res Commun 248: 361-367, 1998

    Google Scholar 

  46. Bonaccorsi L, Carloni V, Muratori M, Salvadori A, Giannini A, Carini M, Serio M, Forti G, Baldi E: Androgen receptor expression in prostate carcinoma cells suppresses alpha6beta4 integrin-mediated invasive phenotype. Endocrinology 141: 3172-3182, 2000

    Google Scholar 

  47. Shen R, Sumitomo M, Dai J, Harris A, Kaminetzky D, Gao M, Burnstein KL, Nanus DM: Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase Endocrinology 141: 1699-1704, 2000

    Google Scholar 

  48. Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL: Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol Cell Biol 19: 5143-5154, 1999

    Google Scholar 

  49. Lavrovsky Y, Mubiru J, Song CS, Ahn SC, Sharp ZD, Herbert DC, Chatterjee B, Roy AK: Aberarnt Prostatic Cell Proliferation in Transgenic Mice Overexpressing Androgen Receptor. 83rd Annual Endocrine Society Meeting, 2001

  50. Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP: Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci USA 98: 10823-10828, 2001

    Google Scholar 

  51. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T: Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61: 3550-3555, 2001

    Google Scholar 

  52. Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM: Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92: 3439-3443, 1995

    Google Scholar 

  53. Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS, Dodd JG, Duckworth ML, Matusik RJ: Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: A model for prostate cancer. Lab Invest 78: i-xv, 1998

    Google Scholar 

  54. Buchanan G, Greenberg NM, Scher HI, Harris JM, Marshall VR, Tilley WD: Collocation of androgen receptor gene mutations in prostate cancer. Clin Cancer Res 5: 1273-1281, 2001

    Google Scholar 

  55. Buchanan G, Yang M, Harris JM, Nahm HS, Han G, Moore N, Bentel JM, Matusik RJ, Horsfall DJ, Marshall VR, Greenberg NM, Tilley WD: Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function. Mol Endocrinol 15: 46-56, 2001

    Google Scholar 

  56. Mononen N, Syrjakoski K, Matikainen M, Tammela TL, Schleutker J, Kallioniemi OP, Trapman J, Koivisto PA: Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene. Cancer Res 60: 6479-64881, 2000

    Google Scholar 

  57. Miyamoto H, Yeh S, Lardy H, Messing E, Chang C: Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci USA 95: 11083-11088, 1998

    Google Scholar 

  58. Gregory CW, Johnson RT Jr, Presnell SC, Mohler JL, French FS: Androgen receptor regulation of G1 cyclin and cyclin-dependent kinase function in the CWR22 human prostate cancer xenograft. J Androl 22: 537-548, 2001

    Google Scholar 

  59. Gnanapragasam VJ, Leung H, Pulimood AS, Neal D, Robson CN: Expression of RAC3, a steroid hormone receptor coactivator in prostate cancer. Br J Cancer 85: 1928-1936, 2001

    Google Scholar 

  60. Fujimoto N, Mizokami A, Harada S, Matsumoto T: Different expression of androgen receptor coactivators in human prostate. Urology 58: 289-294, 2001

    Google Scholar 

  61. Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G, Klocker H, Culig Z: Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res 58: 4640-4645, 1998

    Google Scholar 

  62. Pearson G, Robinson F, Beers Gibson T, Xu Be, Karandikar M, Berman K, Cobb MH: Mitogen-activated protein (map) kinase pathways: Regulation and physiological functions. Endocr Rev 22: 153-183, 2001

    Google Scholar 

  63. Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ: Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59: 279-284, 1999

    Google Scholar 

  64. Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489-501, 2002

    Google Scholar 

  65. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, Kreisberg JI: Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 4: 1168-1171, 2002

    Google Scholar 

  66. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC: Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318-1321, 1998

    Google Scholar 

  67. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687-689, 1997

    Google Scholar 

  68. Sharma M, Chuang WW, Sun Z: Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 277: 30935-30941, 2002

    Google Scholar 

  69. Maehama T, Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375-13378, 1998

    Google Scholar 

  70. Weihua Z, Warner M, Gustafsson J: Estrogen receptor beta in the prostate. Mol Cell Endocrinol 193: 1, 2002

    Google Scholar 

  71. Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F: Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J 19: 5406-5417, 2000

    Google Scholar 

  72. Wang LG, Ossowski L, Ferrari AC: Overexpressed androgen receptor linked to p21WAF1 silencing may be responsible for androgen independence and resistance to apoptosis of a prostate cancer cell line. Cancer Res 61: 7544-7551, 2001

    Google Scholar 

  73. Miyake H, Tolcher A, Gleave ME: Antisense Bcl-2 oligodeoxy-nucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. Cancer Res 59: 4030-4034, 1999

    Google Scholar 

  74. Banerjee D: Technology evaluation: G-3139. Curr Opin Mol Ther 1: 404-408, 1999

    Google Scholar 

  75. Chen S, Song, CS, Lavrovsky Y, Bi B, Vellanoweth R, Chatterjee B, Roy AK: Catalytic cleavage of androgen receptor mRNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. Mol Endocrinol 12: 1558-1566, 1998

    Google Scholar 

  76. Matzke M, Matzke AJ, Kooter JM. RNA: Guiding gene silencing. Science 293: 1080-1083, 2001

    Google Scholar 

  77. Nishikura K: A short primer on RNAi: RNA-directed RNA polymerase acts as a key catalyst. Cell 107: 415-418, 2001

    Google Scholar 

  78. Tuschl T: RNA interference and small interfering RNAs. Chembiochem 2: 239-245, 2001

    Google Scholar 

  79. Sui G, Soohoo C, Affar el B, Gay F, Shi Y, Forrester WC, Shi Y: A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc Natl Acad Sci USA 99: 5515-5520, 2002

    Google Scholar 

  80. Brummelkamp TR, Bernards R, Agami R: A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550-553, 2002

    Google Scholar 

  81. Lee S, Kim H, Yu R, Lee K, Gardner T, Jung C, Jeng M, Yeung F, Cheng L, Kao C: Novel prostate-specific promoter derived from PSA and PSMA enhancers. Mol Ther 6: 415-421, 2002

    Google Scholar 

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  1. Institute of Biotechnology, Department of Molecular Medicine, The University of Texas Health Science, Center, San Antonio, TX, USA

    Bandana Chatterjee

  2. South Texas Veterans Health Care System, San Antonio, TX, USA

    Bandana Chatterjee

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Chatterjee, B. The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Mol Cell Biochem 253, 89–101 (2003). https://doi.org/10.1023/A:1026057402945

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