Skip to main content
SpringerLink
Log in

Androgen Receptor Biology in Prostate Cancer

  • Chapter
  • First Online:
Drug Management of Prostate Cancer

Abstract

Androgens are essential development and survival factors for prostate epithelial cells. Prostate cancer cells retain androgen dependence and, for some period of time, are suppressed by androgen deprivation. Castration-resistant prostate cancer (CRPC) arises after a period of androgen withdrawal and represents the most advanced stage of the disease. CRPC is mediated by the reactivation of androgen receptor activity in the castrate patient. Androgen receptor is reactivated in CRPC by a variety of mechanisms, the breadth of which underscores the importance of androgen receptor for prostate cancer cell proliferation at all stages of the disease. Androgen receptor gene may be affected by the amplification of the locus on the X chromosome or by the activation of mutations. Androgen receptor protein may be phosphorylated by a variety of kinases to enhance its activity in the presence of subphysiologic concentrations of ligand. The cancer cells themselves may produce sufficient levels of androgenic steroids to sustain receptor activation. Androgen receptor activity may also be enhanced by the overexpression of coactivator proteins that allow the formation of the transcriptional complex after the androgen receptor binds to DNA. Lastly, androgen receptor mRNA may be subjected to alternative splicing that may generate ligand-independent truncated forms of activated androgen receptor protein. Thus CRPC cells reactivate androgen receptor as a critical pathway towards cancer progression.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310(5748):644–648.

    Article  PubMed  CAS  Google Scholar 

  2. Tomlins SA, Laxman B, Varambally S et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 2008; 10(2):177–188.

    Article  PubMed  CAS  Google Scholar 

  3. Huggins C, Stevens RE, Hodges CL. Studies on prostatic cancer II. The effect of castration on clinical patients with carcinoma of the prostate. Arch Surg 1941; 43:209.

    Article  CAS  Google Scholar 

  4. Huggins C, Hodges CV. Studies on prostatic cancer; effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293–297.

    CAS  Google Scholar 

  5. Sadi MV, Walsh PC, Barrack ER. Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. Cancer 1991; 67:3057–3064.

    Article  PubMed  CAS  Google Scholar 

  6. Trachtenberg J, Walsh PC. Correlation of prostatic nuclear androgen receptor content with duration of response and survival following hormonal therapy in advanced prostatic cancer. J Urol 1982; 127(3):466–471.

    PubMed  CAS  Google Scholar 

  7. Gonor SE, Lakey WH, McBlain WA. Relationship between concentrations of extractable and matrix-bound nuclear androgen receptor and clinical response to endocrine therapy for prostatic adenocarcinoma. J Urol 1984; 131(6):1196–1201.

    PubMed  CAS  Google Scholar 

  8. Benson RC, Jr., Gorman PA, O’Brien PC, Holicky EL, Veneziale CM. Relationship between androgen receptor binding activity in human prostate cancer and clinical response to endocrine therapy. Cancer 1987; 59(9):1599–1606.

    Article  PubMed  Google Scholar 

  9. Rennie PS, Bruchovsky N, Goldenberg SL. Relationship of androgen receptors to the growth and regression of the prostate. Am J Clin Oncol 1988; 11:S13.

    Article  PubMed  Google Scholar 

  10. Castellanos JM, Galan A, Calvo MA, Schwartz S. Predicting response of prostatic carcinoma to endocrine therapy. Lancet 1982; 1(8269):448.

    Article  PubMed  CAS  Google Scholar 

  11. Chen CD, Welsbie DS, Tran C et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10(1):33–39.

    Article  PubMed  CAS  Google Scholar 

  12. Roy AK, Lavrovsky Y, Song CS et al. Regulation of androgen action. Vitam Horm 1999; 55:309–352.

    Article  PubMed  CAS  Google Scholar 

  13. Gelmann EP. Androgen receptor mutations in prostate cancer. Cancer Treat Res 1996; 87:285–302.

    Article  PubMed  CAS  Google Scholar 

  14. Chang C, Saltzman A, Yeh S et al. Androgen receptor: an overview. Crit Rev Eukaryot Gene Expr 1995; 5(2):97–125.

    Article  PubMed  CAS  Google Scholar 

  15. Lindzey J, Kumar MV, Grossman M, Young C, Tindall DJ. Molecular mechanisms of androgen action. Vitam Horm 1994; 49:383–432.

    Article  PubMed  CAS  Google Scholar 

  16. Quigley CA, De Bellis A, Marschke KB, el Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995; 16(3):271–321.

    PubMed  CAS  Google Scholar 

  17. Buchanan G, Greenberg NM, Scher HI, Harris JM, Marshall VR, Tilley WD. Collocation of androgen receptor gene mutations in prostate cancer. Clin Cancer Res 2001; 7(5):1273–1281.

    PubMed  CAS  Google Scholar 

  18. Janne OA, Moilanen AM, Poukka H et al. Androgen-receptor-interacting nuclear proteins. Biochem Soc Trans 2000; 28(4):401–405.

    Article  PubMed  CAS  Google Scholar 

  19. Taplin ME, Ho SM. Clinical review 134: the endocrinology of prostate cancer. J Clin Endocrinol Metab 2001; 86(8):3467–3477.

    Article  PubMed  CAS  Google Scholar 

  20. Bentel JM, Tilley WD. Androgen receptors in prostate cancer. J Endocrinol 1996; 151(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  21. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 1988; 240(4850):327–330.

    Article  PubMed  CAS  Google Scholar 

  22. Brown CJ, Goss SJ, Lubahn DB et al. Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet 1989; 44(2):264–269.

    PubMed  CAS  Google Scholar 

  23. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 2000; 85(8):2664–2669.

    Article  PubMed  CAS  Google Scholar 

  24. Lubahn DB, Brown TR, Simental JA et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci U S A 1989; 86(23):9534–9538.

    Article  PubMed  CAS  Google Scholar 

  25. Kuiper GG, Faber PW, van Rooij HC et al. Structural organization of the human androgen receptor gene. J Mol Endocrinol 1989; 2(3):R1–R4.

    Article  PubMed  CAS  Google Scholar 

  26. Faber PW, van Rooij HC, Schipper HJ, Brinkmann AO, Trapman J. Two different, overlapping pathways of transcription initiation are active on the TATA-less human androgen receptor promoter. The role of Sp1. J Biol Chem 1993; 268(13):9296–9301.

    PubMed  CAS  Google Scholar 

  27. Tilley WD, Marcelli M, Wilson JD, McPhaul MJ. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A 1989; 86:327–331.

    Article  PubMed  CAS  Google Scholar 

  28. Spencer JA, Watson JM, Lubahn DB et al. The androgen receptor gene is located on a highly conserved region of the X chromosomes of marsupial and monotreme as well as eutherian mammals. J Hered 1991; 82(2):134–139.

    PubMed  CAS  Google Scholar 

  29. Choong CS, Kemppainen JA, Wilson EM. Evolution of the primate androgen receptor: a structural basis for disease. J Mol Evol 1998; 47(3):334–342.

    Article  PubMed  CAS  Google Scholar 

  30. Matias PM, Donner P, Coelho R et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem 2000; 275(34):26164–26171.

    Article  PubMed  CAS  Google Scholar 

  31. Sack JS, Kish KF, Wang C et al. 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 U S A 2001; 98(9):4904–4909.

    Article  PubMed  CAS  Google Scholar 

  32. Shiau AK, Barstad D, Loria PM et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998; 95(7):927–937.

    Article  PubMed  CAS  Google Scholar 

  33. Brzozowski AM, Pike AC, Dauter Z et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389(6652):753–758.

    Article  PubMed  CAS  Google Scholar 

  34. Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc Natl Acad Sci U S A 1998; 95(11):5998–6003.

    Article  PubMed  CAS  Google Scholar 

  35. Nolte RT, Wisely GB, Westin S et al. Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-gamma. Nature 1998; 395(6698):137–143.

    Article  PubMed  CAS  Google Scholar 

  36. Wong CI, Zhou ZX, Sar M, Wilson EM. Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains. J Biol Chem 1993; 268(25):19004–19012.

    PubMed  CAS  Google Scholar 

  37. Langley E, Zhou ZX, Wilson EM. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem 1995; 270(50):29983–29990.

    Article  PubMed  CAS  Google Scholar 

  38. Liao M, Zhou Z, Wilson EM. Redox-dependent DNA binding of the purified androgen receptor: evidence for disulfide-linked androgen receptor dimers. Biochemistry 1999; 38(30):9718–9727.

    Article  PubMed  CAS  Google Scholar 

  39. Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem 1991; 266(1):510–518.

    PubMed  CAS  Google Scholar 

  40. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352(6330):77–79.

    Article  PubMed  Google Scholar 

  41. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004; 25(2):276–308.

    Article  PubMed  CAS  Google Scholar 

  42. Hsiao PW, Lin DL, Nakao R, Chang C. The linkage of Kennedy’s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 1999; 274(29):20229–20234.

    Article  PubMed  CAS  Google Scholar 

  43. Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, Coetzee GA. Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet 2000; 9(2):267–274.

    Article  PubMed  CAS  Google Scholar 

  44. Sartor O, Zheng Q, Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology 1999; 53(2):378–380.

    Article  PubMed  CAS  Google Scholar 

  45. Andersson P, Varenhorst E, Soderkvist P. Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. Eur J Cancer 2006; 42(16):2833–2837.

    Article  PubMed  CAS  Google Scholar 

  46. Silva NB, Koff WJ, Biolchi V et al. Polymorphic CAG and GGC repeat lengths in the androgen receptor gene and prostate cancer risk: analysis of a Brazilian population. Cancer Invest 2008; 26(1):74–80.

    Article  CAS  Google Scholar 

  47. Mittal RD, Mishra D, Mandhani AK. Role of an androgen receptor gene polymorphism in development of hormone refractory prostate cancer in Indian population. Asian Pac J Cancer Prev 2007; 8(2):275–278.

    PubMed  Google Scholar 

  48. Patino-Garcia B, Arroyo C, Rangel-Villalobos H et al. Association between polymorphisms of the androgen and vitamin D receptor genes with prostate cancer risk in a Mexican population. Rev Invest Clin 2007; 59(1):25–31.

    PubMed  CAS  Google Scholar 

  49. Krishnaswamy V, Kumarasamy T, Venkatesan V, Shroff S, Jayanth VR, Paul SF. South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer. J Hum Genet 2006; 51(3):254–257.

    Article  PubMed  CAS  Google Scholar 

  50. Giwercman C, Giwercman A, Pedersen HS et al. Polymorphisms in genes regulating androgen activity among prostate cancer low-risk Inuit men and high-risk Scandinavians. Int J Androl 2008; 31(1):25–30.

    PubMed  CAS  Google Scholar 

  51. Buchanan G, Yang M, Cheong A et al. Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet 2004; 13(16):1677–1692.

    Article  PubMed  CAS  Google Scholar 

  52. Robins DM, Albertelli MA, O’Mahony OA. Androgen receptor variants and prostate cancer in humanized AR mice. J Steroid Biochem Mol Biol 2008; 108(3–5):230–236.

    Article  PubMed  CAS  Google Scholar 

  53. Visakorpi T, Hyytinen E, Koivisto P et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995; 9(4):401–406.

    Article  PubMed  CAS  Google Scholar 

  54. Koivisto P, Visakorpi T, Kallioniemi OP. Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand J Clin Lab Invest Suppl 1996; 226:57–63.

    PubMed  CAS  Google Scholar 

  55. Miyoshi Y, Uemura H, Fujinami K et al. Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients. Prostate 2000; 43(3):225–232.

    Article  PubMed  CAS  Google Scholar 

  56. 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 2001; 61(9):3550–3555.

    PubMed  CAS  Google Scholar 

  57. Palmberg C, Koivisto P, Hyytinen E et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur Urol 1997; 31(2):216–219.

    PubMed  CAS  Google Scholar 

  58. Taplin ME, Bubley GJ, Shuster TD et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995; 332(21):1393–1398.

    Article  PubMed  CAS  Google Scholar 

  59. Taplin ME, Bubley GJ, Ko YJ et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 1999; 59(11):2511–2515.

    PubMed  CAS  Google Scholar 

  60. Tilley WD, Buchanan G, Hickey TE, Bentel JM. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res 1996; 2(2):277–285.

    PubMed  CAS  Google Scholar 

  61. Tan J, Sharief Y, Hamil KG et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 1997; 11(4):450–459.

    Article  PubMed  CAS  Google Scholar 

  62. Marcelli M, Ittmann M, Mariani S et al. Androgen receptor mutations in prostate cancer. Cancer Res 2000; 60(4):944–949.

    PubMed  CAS  Google Scholar 

  63. Barrack ER. Androgen receptor mutations in prostate cancer. Mt Sinai J Med 1996; 63(5–6):403–412.

    PubMed  CAS  Google Scholar 

  64. Culig Z, Hobisch A, Hittmair A et al. Androgen receptor gene mutations in prostate cancer. Implications for disease progression and therapy. Drugs Aging 1997; 10(1):50–58.

    Article  PubMed  CAS  Google Scholar 

  65. Wang C, Uchida T. [Androgen receptor gene mutations in prostate cancer]. Nippon Hinyokika Gakkai Zasshi 1997; 88(5):550–556.

    PubMed  CAS  Google Scholar 

  66. Suzuki H, Sato N, Watabe Y, Masai M, Seino S, Shimazaki J. Androgen receptor gene mutations in human prostate cancer. J Steroid Biochem Mol Biol 1993; 46(6):759–765.

    Article  PubMed  CAS  Google Scholar 

  67. Newmark JR, Hardy DO, Tonb DC et al. Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci U S A 1992; 89(14):6319–6323.

    Article  PubMed  CAS  Google Scholar 

  68. Wallen MJ, Linja M, Kaartinen K, Schleutker J, Visakorpi T. Androgen receptor gene mutations in hormone-refractory prostate cancer. J Pathol 1999; 189(4):559–563.

    Article  PubMed  CAS  Google Scholar 

  69. Castagnaro M, Yandell DW, Dockhorn-Dworniczak B, Wolfe HJ, Poremba C. [Androgen receptor gene mutations and p53 gene analysis in advanced prostate cancer]. Verh Dtsch Ges Pathol 1993; 77:119–123.

    PubMed  CAS  Google Scholar 

  70. Veldscholte J, Voorhorst-Ogink MM, Bolt-de Vries J, van Rooij HC, Trapman J, Mulder E. Unusual specificity of the androgen receptor in the human prostate tumor cell line LNCaP: high affinity for progestagenic and estrogenic steroids. Biochim Biophys Acta 1990; 1052(1):187–194.

    Article  PubMed  CAS  Google Scholar 

  71. De BA, Quigley CA, Cariello NF et al. Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique. Mol Endocrinol 1992; 6(11):1909–1920.

    Article  Google Scholar 

  72. Jakubiczka S, Werder EA, Wieacker P. Point mutation in the steroid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome (CAIS). Hum Genet 1992; 90(3):311–312.

    Article  PubMed  CAS  Google Scholar 

  73. Ahmed SF, Cheng A, Dovey L et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab 2000; 85(2):658–665.

    Article  PubMed  CAS  Google Scholar 

  74. Van YH, Lin JL, Huang SF, Luo CC, Hwang CS, Lo FS. Novel point mutations in complete androgen insensitivity syndrome with incomplete mullerian regression: two Taiwanese patients. Eur J Pediatr 2003; 162(11):781–784.

    Article  PubMed  CAS  Google Scholar 

  75. Bouvattier C, Carel JC, Lecointre C et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab 2002; 87(1):29–32.

    Article  PubMed  CAS  Google Scholar 

  76. Takahashi H, Furusato M, Allsbrook WC, Jr. et al. Prevalence of androgen receptor gene mutations in latent prostatic carcinomas from Japanese men. Cancer Res 1995; 55(8):1621–1624.

    PubMed  CAS  Google Scholar 

  77. Haapala K, Hyytinen ER, Roiha M et al. Androgen receptor alterations in prostate cancer relapsed during a combined androgen blockade by orchiectomy and bicalutamide. Lab Invest 2001; 81(12):1647–1651.

    Article  PubMed  CAS  Google Scholar 

  78. Gregory CW, Johnson RT, Jr., Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 2001; 61(7):2892–2898.

    PubMed  CAS  Google Scholar 

  79. Chen G, Wang X, Zhang S et al. Androgen receptor mutants detected in recurrent prostate cancer exhibit diverse functional characteristics. Prostate 2005; 63(4):395–406.

    Article  PubMed  CAS  Google Scholar 

  80. Jagla M, Feve M, Kessler P et al. A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions. Endocrinology 2007; 148(9):4334–4343

    Article  PubMed  CAS  Google Scholar 

  81. Buchanan G, Yang M, Harris JM et al. Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function. Mol Endocrinol 2001; 15(1):46–56.

    Article  PubMed  CAS  Google Scholar 

  82. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L. Nuclear receptor coactivators and corepressors. Mol Endocrinol 1996; 10(10):1167–1177.

    Article  PubMed  CAS  Google Scholar 

  83. Greenberg NM, DeMayo F, Finegold MJ et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci U S A 1995; 92(8):3439–3443.

    Article  PubMed  CAS  Google Scholar 

  84. Wang Q, Lu J, 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 2001; 276:7493–7499.

    Article  PubMed  CAS  Google Scholar 

  85. He B, Bowen NT, Minges JT, Wilson EM. Androgen-induced NH2- and COOH-terminal Interaction Inhibits p160 coactivator recruitment by activation function 2. J Biol Chem 2001; 276(45):42293–42301.

    Article  PubMed  CAS  Google Scholar 

  86. Gregory CW, Fei X, Ponguta LA et al. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem 2004; 279(8):7119–7130.

    Article  PubMed  CAS  Google Scholar 

  87. Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, Sawyers CL. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell 2004; 6(5):517–527.

    Article  PubMed  CAS  Google Scholar 

  88. Gregory CW, Whang YE, McCall W et al. Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res 2005; 11(5):1704–1712.

    Article  PubMed  CAS  Google Scholar 

  89. Liu Y, Majumder S, McCall W et al. Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res 2005; 65(8):3404–3409.

    PubMed  CAS  Google Scholar 

  90. Mahajan NP, Liu Y, Majumder S et al. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A 2007; 104(20):8438–8443.

    Article  PubMed  CAS  Google Scholar 

  91. Ponguta LA, Gregory CW, French FS, Wilson EM. Site specific androgen receptor serine phosphorylation linked to epidermal growth factor dependent growth of castration-recurrent prostate cancer. J Biol Chem 2008; 283(30):20989–21001.

    Article  PubMed  CAS  Google Scholar 

  92. Sun M, Yang L, Feldman RI et al. Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src. J Biol Chem 2003; 278(44):42992–43000.

    Article  PubMed  CAS  Google Scholar 

  93. Guo Z, Dai B, Jiang T et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 2006; 10(4):309–319.

    Article  PubMed  CAS  Google Scholar 

  94. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 2008; 68(13):5469–5477.

    Article  PubMed  CAS  Google Scholar 

  95. Mohler JL, Gregory CW, Ford OH, III et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004; 10(2):440–448.

    Article  PubMed  CAS  Google Scholar 

  96. Stanbrough M, Bubley GJ, Ross K et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 2006; 66(5):2815–2825.

    Article  PubMed  CAS  Google Scholar 

  97. Locke JA, Guns ES, Lubik AA et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008; 68(15):6407–6415.

    Article  PubMed  CAS  Google Scholar 

  98. Trachtenberg J, Halpern N, Pont A. Ketoconazole: a novel and rapid treatment for advanced prostatic cancer. J Urol 1983; 130(1):152–153.

    PubMed  CAS  Google Scholar 

  99. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet 1984; 2(8400):433–435.

    Article  PubMed  CAS  Google Scholar 

  100. Small EJ, Halabi S, Dawson NA et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 2004; 22(6):1025–1033.

    Article  PubMed  CAS  Google Scholar 

  101. Attard G, Reid AH, Yap TA et al. 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 2008; 26(28):4563–4571.

    Article  PubMed  CAS  Google Scholar 

  102. O’Donnell A, Judson I, Dowsett M et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 2004; 90(12):2317–2325.

    PubMed  Google Scholar 

  103. Alen P, Claessens F, Verhoeven G, Rombauts W, Peeters B. The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription. Mol Cell Biol 1999; 19(9):6085–6097.

    PubMed  CAS  Google Scholar 

  104. Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer 2007; 120(4):719–733.

    Article  PubMed  CAS  Google Scholar 

  105. Gregory CW, He B, Johnson RT et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 2001; 61(11):4315–4319.

    PubMed  CAS  Google Scholar 

  106. Agoulnik IU, Vaid A, Bingman WE, III et al. Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res 2005; 65(17):7959–7967.

    PubMed  CAS  Google Scholar 

  107. 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 1999; 19(12):8383–8392.

    PubMed  CAS  Google Scholar 

  108. Agoulnik IU, Vaid A, Nakka M et al. Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res 2006; 66(21):10594–10602.

    Article  PubMed  CAS  Google Scholar 

  109. Zhou HJ, Yan J, Luo W et al. SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res 2005; 65(17):7976–7983.

    PubMed  CAS  Google Scholar 

  110. Miyamoto H, Yeh S, Wilding G, Chang C. Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A 1998; 95(13):7379–7384.

    Article  PubMed  CAS  Google Scholar 

  111. Halkidou K, Gnanapragasam VJ, Mehta PB et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 2003; 22(16):2466–2477.

    Article  PubMed  CAS  Google Scholar 

  112. Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY. Overexpression of Cdc25B, an androgen receptor coactivator, in prostate cancer. Oncogene 2003; 22(5):734–739.

    Article  PubMed  CAS  Google Scholar 

  113. Heemers HV, Sebo TJ, Debes JD et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res 2007; 67(7):3422–3430.

    Article  PubMed  CAS  Google Scholar 

  114. Taneja SS, Ha S, Swenson NK et al. ART-27, an androgen receptor coactivator regulated in prostate development and cancer. J Biol Chem 2004; 279(14):13944–13952.

    Article  PubMed  CAS  Google Scholar 

  115. Fujimoto N, Yeh S, Kang HY et al. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem 1999; 274(12):8316–8321.

    Article  PubMed  CAS  Google Scholar 

  116. Wang X, Yang Y, Guo X et al. Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator. J Biol Chem 2002; 277(18):15426–15431.

    Article  PubMed  CAS  Google Scholar 

  117. Voeller HJ, Truica CI, Gelmann EP. Beta-catenin mutations in human prostate cancer. Cancer Res 1998; 58(12):2520–2523.

    PubMed  CAS  Google Scholar 

  118. Chesire DR, Ewing CM, Sauvageot J, Bova GS, Isaacs WB. Detection and analysis of beta-catenin mutations in prostate cancer. Prostate 2000; 45(4):323–334.

    Article  PubMed  CAS  Google Scholar 

  119. Watanabe M, Kakiuchi H, Kato H et al. APC gene mutations in human prostate cancer. Jpn J Clin Oncol 1996; 26(2):77–81.

    Article  PubMed  CAS  Google Scholar 

  120. Gerstein AV, Almeida TA, Zhao G et al. APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers. Genes Chromosomes Cancer 2002; 34(1):9–16.

    Article  PubMed  CAS  Google Scholar 

  121. Henrique R, Ribeiro FR, Fonseca D et al. High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin Cancer Res 2007; 13(20):6122–6129.

    Article  PubMed  CAS  Google Scholar 

  122. Mulholland DJ, Dedhar S, Wu H, Nelson CC. PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. Oncogene 2006; 25(3):329–337.

    Article  PubMed  CAS  Google Scholar 

  123. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 1996; 272(5264):1023–1026.

    Article  PubMed  CAS  Google Scholar 

  124. Rios-Doria J, Kuefer R, Ethier SP, Day ML. Cleavage of beta-catenin by calpain in prostate and mammary tumor cells. Cancer Res 2004; 64(20):7237–7240.

    Article  PubMed  CAS  Google Scholar 

  125. Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res 2000; 60(17):4709–4713.

    PubMed  CAS  Google Scholar 

  126. Yang F, Li X, Sharma M et al. Linking beta-catenin to androgen-signaling pathway. J Biol Chem 2002; 277(13):11336–11344.

    Article  PubMed  CAS  Google Scholar 

  127. Mulholland DJ, Cheng H, Reid K, Rennie PS, Nelson CC. The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. J Biol Chem 2002; 277(20):17933–17943.

    Article  PubMed  CAS  Google Scholar 

  128. Pawlowski JE, Ertel JR, Allen MP et al. Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells. J Biol Chem 2002; 277(23):20702–20710.

    Article  PubMed  CAS  Google Scholar 

  129. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP. Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription. Mol Cell Biol 2003; 23(5):1674–1687.

    Article  PubMed  CAS  Google Scholar 

  130. Song LN, Gelmann EP. Interaction of {beta}-Catenin and TIF2/GRIP1 in transcriptional activation by the androgen receptor. J Biol Chem 2005; 280(45):37853–37867.

    Article  PubMed  CAS  Google Scholar 

  131. Liao G, Chen LY, Zhang A et al. Regulation of androgen receptor activity by the nuclear receptor corepressor SMRT. J Biol Chem 2003; 278(7):5052–5061.

    Article  PubMed  CAS  Google Scholar 

  132. Song LN, Coghlan M, Gelmann EP. Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. Mol Endocrinol 2004; 18(1):70–85.

    Article  PubMed  CAS  Google Scholar 

  133. Masiello D, Chen SY, Xu Y et al. Recruitment of beta-catenin by wild-type or mutant androgen receptors correlates with ligand-stimulated growth of prostate cancer cells. Mol Endocrinol 2004; 18(10):2388–2401.

    Article  PubMed  CAS  Google Scholar 

  134. Hodgson MC, Astapova I, Hollenberg AN, Balk SP. Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors. Cancer Res 2007; 67(17):8388–8395.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    Edward P. Gelmann

Authors
  1. Edward P. Gelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward P. Gelmann .

Editor information

Editors and Affiliations

  1. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    William D. Figg

  2. Medical Oncology Branch, NIH National Cancer Institute, Rockville Pike 9000, Bethesda, 20892, Maryland, USA

    Cindy H. Chau

  3. School of Medicine, Dept. Urology, University of California, San Francisco, Divisadero Street 1600, San Francisco, 94115, California, USA

    Eric J. Small

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Gelmann, E.P. (2010). Androgen Receptor Biology in Prostate Cancer. In: Figg, W., Chau, C., Small, E. (eds) Drug Management of Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-60327-829-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-829-4_5

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-60327-831-7

  • Online ISBN: 978-1-60327-829-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation