Skip to main content

Advertisement

SpringerLink
Log in

Androgen receptor: what we know and what we expect in castration-resistant prostate cancer

  • Urology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Androgen deprivation therapy is an important therapy for prostate cancer (PCa) in aging men. Under the background of castration, it is inevitable that prostate cancer will develop into castration-resistant prostate cancer (CRPC), which has a high mortality rate, after 2–3 years. Androgen receptor (AR) plays a key role in PCa development and is essential to CRPC. More recent research studies have reported that the development of CRPC is largely due to altered mechanisms related to AR, so it is important for us to understand the roles of AR and detailed AR-related mechanisms in CRPC. The multiple AR-related mechanisms promoting the development of CRPC are as follows: (1) enhanced transformation and increased synthesis of intratumoral androgen; (2) AR overexpression, which enables CRPC to be hypersensitive to low levels of androgen; (3) AR cofactors, which enhanced AR transactivation; (4) AR-spliced variants, which mediated downstream gene expression without androgen; (5) the interaction between the AR pathway and classic tumor-related pathways; and» (6) AR mutations, which reduced AR specificity and enhanced AR transcription.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  2. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  3. Perner S, Cronauer MV, Schrader AJ, Klocker H, Culig Z, Baniahmad A (2015) Adaptive responses of androgen receptor signaling in castration-resistant prostate cancer. Oncotarget 6(34):35542–35555

    Article  PubMed Central  PubMed  Google Scholar 

  4. Mimeault M, Batra SK (2006) Recent advances on multiple tumor igenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis 27:1–22

    Article  CAS  PubMed  Google Scholar 

  5. Galletti G, Leach BI, Lam L, Tagawa ST (2017) Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer. Cancer Treat Rev 57:16–27

    Article  CAS  PubMed  Google Scholar 

  6. Kim NC, Anders B, David D, Saad F, Schröder FH, Sternberg C, Tombal B, Visakorpi T (2009) Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol 56:594–605

    Article  CAS  Google Scholar 

  7. Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, Corey E, Nanus DM, Plymate SR, Giannakakou P (2014) Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 74:2270–2282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, van der Poel HG, van der Kwast TH, Rouvière O, Wiegel T, Mottet N (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol 71(4):630–642

    Article  PubMed  Google Scholar 

  9. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J (2012) Androgen insensitivity syndrome. Lancet 380:1419–1428

    Article  CAS  PubMed  Google Scholar 

  10. Shafi AA, Yen AE, Weigel NL (2013) Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther 140:223–238

    Article  CAS  PubMed  Google Scholar 

  11. Wang Q, Li W, Zhang Y et al (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138:245–256

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Koochekpour S (2010) Androgen receptor signaling and mutations in prostate cancer. Asian J Androl 12:639–657

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Wolf IM, Heitzer MD, Grubisha M, DeFranco DB (2008) Coactivators and nuclear receptor transactivation. J Cell Biochem 104:1580–1586

    Article  CAS  PubMed  Google Scholar 

  14. Heemers HV, Tindall DJ (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28(7):778–808

    Article  CAS  PubMed  Google Scholar 

  15. Ni L, Yang CS, Gioeli D, Frierson H, Toft DO, Paschal BM (2010) FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol 30:1243–1253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Culig Z, Santer FR (2018) Studies on steroid receptor coactivators in prostate cancer. Methods Mol Biol 1786:259–262

    Article  PubMed  Google Scholar 

  17. Debes JD, Schmidt LJ, Huang H, Tindall DJ (2002) p300 mediates androgen-independent trans-activation of the androgen receptor by interleukin 6. Cancer Res 62:5632–5636

    CAS  PubMed  Google Scholar 

  18. Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Günther T, Buettner R, Metzger E, Schüle R (2007) Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 9:347–353

    Article  CAS  PubMed  Google Scholar 

  19. Wijngaart DJVD, Dubbink HJ, Royen MEV, Trapman J, Jenster G (2012) Androgen receptor coregulators: Recruitment via the coactivator binding groove. Mol Cell Endocrinol 352(1–2):57–69

    Article  CAS  PubMed  Google Scholar 

  20. Sonoda J, Pei L, Evans RM (2008) Nuclear receptors: decoding metabolic disease. FEBS Lett 582(1):2–9

    Article  CAS  PubMed  Google Scholar 

  21. Wang K, Ruan H, Xu T, Liu L, Liu D, Yang H, Zhang X, Chen K (2018) Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer. Onco Targets Ther 11:3167–3178

    Article  PubMed Central  PubMed  Google Scholar 

  22. Hettel D, Zhang A, Alyamani M, Berk M, Sharifi N (2018) AR signaling in prostate cancer regulates a feed-forward mechanism of androgen synthesis by way of HSD3B1 upregulation. Endocrinology 159(8):2884–2890

    Article  PubMed Central  PubMed  Google Scholar 

  23. Chen WY, Tsai YC, Siu MK, Yeh HL, Chen CL, Yin JJ, Huang J, Liu YN (2017) Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis. Oncogene 36(45):6213–6224

    Article  CAS  PubMed  Google Scholar 

  24. Vander Ark A, Cao J, Li X (2018) Mechanisms and approaches for overcoming enzalutamide resistance in prostate cancer. Front Oncol 8:180

    Article  PubMed Central  PubMed  Google Scholar 

  25. Haelens A, Tanner T, Denayer S, Callewaert L, Claessens F (2007) The hinge region regulates DNA binding, nuclear translocation, and transactivation of the androgen receptor. Cancer Res 67(9):4514–4523

    Article  CAS  PubMed  Google Scholar 

  26. Zhou J, Liu B, Geng G, Wu JH (2010) Study of the impact of the T877A mutation on ligand-induced helix-12 positioning of the androgen receptor resulted in design and synthesis of novel anti-androgens. Proteins 78(3):623–637

    CAS  PubMed  Google Scholar 

  27. Wadosky KM, Koochekpour S (2016) Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer. Oncotarget 7(39):64447–64470

    Article  PubMed Central  PubMed  Google Scholar 

  28. Barron DA, Rowley DR (2012) The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer 19:R187–R204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Banerjee PP, Banerjee S, Brown TR, Zirkin BR (2018) Androgen action in prostate function and disease. Am J Clin Exp Urol 6(2):62–77

    PubMed  PubMed Central  Google Scholar 

  30. Bremmer F, Jarry H, Unterkircher V, Kaulfuss S, Burfeind P, Radzun HJ, Ströbel P, Thelen P (2018) Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer. Oncotarget 9(24):16951–16961

    Article  PubMed Central  PubMed  Google Scholar 

  31. Labrie F, Luu-The V, Bélanger A, Lin SX, Simard J, Pelletier G, Labrie C (2005) Is dehydroepiandrosterone a hormone? J Endocrinol 187(2):169–196

    Article  CAS  PubMed  Google Scholar 

  32. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68:4447–4454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kohli M, Li J, Du M, Hillman DW, Dehm SM, Tan W, Carlson R, Campion MB, Wang L, Wang L, Zhang H, Zhang P, Kilari D, Huang CC, Wang L (2018) Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients. Prostate Cancer Prostatic Dis. https://doi.org/10.1038/s41391-018-0043-z

    Article  PubMed  PubMed Central  Google Scholar 

  34. Salvi S, Casadio V, Conteduca V, Lolli C, Gurioli G, Martignano F, Schepisi G, Testoni S, Scarpi E, Amadori D, Calistri D, Attard G, De Giorgi U (2016) Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget 7(25):37839–37845

    Article  PubMed Central  PubMed  Google Scholar 

  35. Wang F, Koul HK (2017) Androgen receptor (AR) cistrome in prostate differentiation and cancer progression. Am J Clin Exp Urol 5(3):18–24

    PubMed  PubMed Central  Google Scholar 

  36. Liu W, Xie CC, Zhu Y, Li T, Sun J, Cheng Y, Ewing CM, Dalrymple S, Turner AR, Sun J, Isaacs JT, Chang BL, Zheng SL, Isaacs WB, Xu J (2008) Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasi 10:897–907

    Article  CAS  Google Scholar 

  37. Taylor BS, Schultz N, Hieronymus H et al (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP (1999) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9:401–406

    Article  Google Scholar 

  39. Chen Y, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmaco 8:440–448

    Article  CAS  Google Scholar 

  40. Shiota M, Takeuchi A, Song Y, Yokomizo A, Kashiwagi E, Uchiumi T, Kuroiwa K, Tatsugami K, Fujimoto N, Oda Y, Naito S (2011) Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression. Endocr Relat Cancer 18(4):505–517

    Article  CAS  PubMed  Google Scholar 

  41. Huang WC, Li X, Liu J, Lin J, Chung LW (2012) Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells. Mol Cancer Res 10(1):133–142

    Article  CAS  PubMed  Google Scholar 

  42. Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, Eto M, Uchiumi T, Naito S (2010) Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene 29(2):237–250

    Article  CAS  PubMed  Google Scholar 

  43. Santer FR, Erb HH, McNeill RV (2015) Therapy escape mechanisms in the malignant prostate. Semin Cancer Biol 35:133–144

    Article  PubMed  Google Scholar 

  44. Ueda T, Mawji NR, Bruchovsky N, Sadar MD (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

    Article  CAS  PubMed  Google Scholar 

  45. Liu S, Kumari S, Hu Q et al (2017) A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer. Elife 6:e33738

    Article  PubMed Central  PubMed  Google Scholar 

  46. Agoulnik IU, Vaid A, Nakka M, Alvarado M, Bingman WE 3rd, Erdem H, Frolov A, Smith CL, Ayala GE, Ittmann MM, Weigel NL (2006) 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 66:10594–10602

    Article  CAS  PubMed  Google Scholar 

  47. Fujimoto N, Miyamoto H, Mizokami A, Harada S, Nomura M, Ueta Y, Sasaguri T, Matsumoto T (2007) Prostate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; a possible mechanism of hormone-resistance of prostate cancer cells. Cancer Invest 25(1):32–37

    Article  CAS  PubMed  Google Scholar 

  48. Sun S, Zhong X, Wang C, Sun H, Wang S, Zhou T, Zou R, Lin L, Sun N, Sun G, Wu Y, Wang B, Song X, Cao L, Zhao Y (2016) BAP18 coactivates androgen receptor action and promotes prostate cancer progression. Nucleic Acids Res 44(17):8112–8128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Wang L, Song G, Zhang X, Feng T, Pan J, Chen W, Yang M, Bai X, Pang Y, Yu J, Han J, Han B (2017) PADI2-mediated citrullination promotes prostate cancer progression. Cancer Res 77(21):5755–5768

    Article  CAS  PubMed  Google Scholar 

  50. Wyatt AW, Gleave ME (2015) Targeting the adaptive molecular landscape of castration-resistant prostate cancer. EMBO Mol Med 7(7):878–894

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715–2730

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, Bova GS, Luo J (2009) Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69(1):16–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Libertini SJ, Tepper CG, Rodriguez V, Asmuth DM, Kung HJ, Mudryj M (2007) Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res 67(19):9001–9005

    Article  CAS  PubMed  Google Scholar 

  54. Chan SC, Li Y, Dehm SM (2012) Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem 287(23):19736–19749

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Hodgson MC, Shao LJ, Frolov A, Li R, Peterson LE, Ayala G, Ittmann MM, Weigel NL, Agoulnik IU (2011) Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res 71:572–582

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y (2009) A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 69:2305–2313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Hörnberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, Bergh A, Wikström P (2011) Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 6(4):e19059

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Welti J, Rodrigues DN, Sharp A, Sun S, Lorente D, Riisnaes R, Figueiredo I, Zafeiriou Z, Rescigno P, de Bono JS, Plymate SR (2016) Analytical validation and clinical qualification of a new immunohistochemical assay for androgen receptor splice variant-7 protein expression in metastatic castration-resistant prostate cancer. Eur Urol 70(4):599–608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Takeuchi T, Okuno Y, Hattori-Kato M, Zaitsu M, Mikami K (2016) Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer. Res Rep Urol 8:21–25

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang JC, Ok JH, Busby JE, Borowsky AD, Kung HJ, Evans CP (2009) Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer. Cancer Res 69:151–160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Qi W, Morales C, Cooke LS, Johnson B, Somer B, Mahadevan D (2015) Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer. Oncotarget 6(39):41976–41987

    Article  PubMed Central  PubMed  Google Scholar 

  62. Toren P, Kim S, Johnson F, Zoubeidi A (2016) Combined AKT and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer. PLoS ONE 11(4):e0152861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, Sawyers CL (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Edlind MP, Hsieh AC (2014) PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl 16(3):378–386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Cohen MB, Rokhlin OW (2009) Mechanisms of prostate cancer cell survival after inhibition of AR expression. J Cell Biochem 106(3):363–371

    Article  CAS  PubMed  Google Scholar 

  66. Smith AM, Findlay VJ, Bandurraga SG, Kistner-Griffin E, Spruill LS, Liu A, Golshayan AR, Turner DP (2012) ETS1 transcriptional activity is increased in advanced prostate cancer and promotes the castrate-resistant phenotype. Carcinogenesis 33(3):572–580

    Article  CAS  PubMed  Google Scholar 

  67. Leung JK, Sadar MD (2017) Non-genomic actions of the androgen receptor in prostate cancer. Front Endocrinol (Lausanne) 8:2

    Google Scholar 

  68. Mukherjee R, McGuinness DH, McCall P, Underwood MA, Seywright M, Orange C, Edwards J (2011) Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer. Br J Cancer 104(12):1920–1928

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Migliaccio A, Castoria G, Auricchio F (2011) Analysis of androgen receptor rapid actions in cellular signaling pathways: receptor/Src association. Methods Mol Biol 776:361–370

    Article  CAS  PubMed  Google Scholar 

  70. Yokoyama NN, Shao S, Hoang BH, Mercola D, Zi X (2014) Wnt signaling in castration-resistant prostate cancer: implications for therapy. Am J Clin Exp Urol 2(1):27–44

    PubMed  PubMed Central  Google Scholar 

  71. Wang G, Wang J, Sadar MD (2008) Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res 68(23):9918–9927

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Zhang Z, Cheng L, Li J, Farah E, Atallah NM, Pascuzzi PE, Gupta S, Liu X (2018) Inhibition of the Wnt/β-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer. Cancer Res 78(12):3147–3162

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang Q, Symes AJ, Kane CA, Freeman A, Nariculam J, Munson P, Thrasivoulou C, Masters JR, Ahmed A (2010) A novel role for Wnt/Ca2+ signaling in actin cytoskeleton remodeling and cell motility in prostate cancer. PLoS ONE 5(5):e10456

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Thompson VC, Hurtado-Coll A, Turbin D, Fazli L, Lehman ML, Gleave ME, Nelson CC (2010) Relaxin drives Wnt signaling through upregulation of PCDHY in prostate cancer. Prostate 70(10):1134–1145

    Article  CAS  PubMed  Google Scholar 

  75. Mohanty SK, Yagiz K, Pradhan D, Luthringer DJ, Amin MB, Alkan S, Cinar B (2017) STAT3 and STAT5A are potential therapeutic targets in castration-resistant prostate cancer. Oncotarget 8(49):85997–86010

    Article  PubMed Central  PubMed  Google Scholar 

  76. Hoang DT, Gu L, Liao Z, Shen F, Talati PG, Koptyra M, Tan SH, Ellsworth E, Gupta S, Montie H, Dagvadorj A, Savolainen S, Leiby B, Mirtti T, Merry DE, Nevalainen MT (2015) Inhibition of Stat5a/b enhances proteasomal degradation of androgen receptor liganded by antiandrogens in prostate cancer. Mol Cancer Ther 14(3):713–726

    Article  CAS  PubMed  Google Scholar 

  77. Thomas C, Zoubeidi A, Kuruma H, Fazli L, Lamoureux F, Beraldi E, Monia BP, MacLeod AR, Thüroff JW, Gleave ME (2011) Transcription factor Stat5 knockdown enhances androgen receptor degradation and delays castration-resistant prostate cancer progression in vivo. Mol Cancer Ther 10(2):347–359

    Article  CAS  PubMed  Google Scholar 

  78. Kobayashi T, Inoue T, Shimizu Y, Terada N, Maeno A, Kajita Y, Yamasaki T, Kamba T, Toda Y, Mikami Y, Yamada T, Kamoto T, Ogawa O, Nakamura E (2010) Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo. Mol Endocrinol 24(4):722–734

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Liu VWS, Yau WL, Tam CW, Yao KM, Shiu SYW (2017) Melatonin inhibits androgen receptor splice variant-7 (AR-V7)-induced nuclear factor-kappa B (NF-κB) activation and NF-κB activator-induced AR-V7 expression in prostate cancer cells: potential implications for the use of melatonin in castration-resistant prostate cancer (CRPC) therapy. Int J Mol Sci 18(6):1130

    Article  PubMed Central  Google Scholar 

  80. Isikbay M, Otto K, Kregel S, Kach J, Cai Y, Vander Griend DJ, Conzen SD, Szmulewitz RZ (2014) Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer 5(2):72–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M (2012) The androgen receptor gene mutations database: 2012 update. Hum Mutat 33:887–894

    Article  CAS  PubMed  Google Scholar 

  82. Karnes RJ, Sharma V, Choeurng V et al (2018) Development and validation of a prostate cancer genomic signature that predicts early ADT treatment response following radical prostatectomy. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-2745

    Article  PubMed  PubMed Central  Google Scholar 

  83. Han D, Gao S, Valencia K, Owiredu J, Han W, de Waal E, Macoska JA, Cai C (2017) A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer. Oncotarget 8(4):6796–6808

    Article  PubMed  Google Scholar 

  84. Bergerat JP, Céraline J (2009) Pleiotropic functional properties of androgen receptor mutants in prostate cancer. Hum Mutat 30:145–157

    Article  CAS  PubMed  Google Scholar 

  85. Clinckemalie L, Vanderschueren D, Boonen S, Claessens F (2012) The hinge region in androgen receptor control. Mol Cell Endocrinol 358(1):1–8

    Article  CAS  PubMed  Google Scholar 

  86. Bohl CE, Wu Z, Miller DD, Bell CE, Dalton JT (2007) Crystal structure of the T877A human androgen receptor ligand-binding domain complexed to cyproterone acetate provides insight for ligand-induced conformational changes and structure-based drug design. J Biol Chem 282:13648–13655

    Article  CAS  PubMed  Google Scholar 

  87. Monge A, Jagla M, Lapouge G, Sasorith S, Cruchant M, Wurtz JM, Jacqmin D, Bergerat JP, Céraline J (2006) Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer. Cell Mol Life Sci 63:487–497

    Article  CAS  PubMed  Google Scholar 

  88. Nazareth LV, Stenoien DL, Bingman WE 3rd, James AJ, Wu C, Zhang Y, Edwards DP, Mancini M, Marcelli M, Lamb DJ, Weigel NL (1999) A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1). Mol Endocrinol 13(12):2065–2075

    Article  CAS  PubMed  Google Scholar 

  89. Jenster G, van der Korput HA, Trapman J, Brinkmann AO (1995) Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 270:7341–7346

    Article  CAS  PubMed  Google Scholar 

  90. Wang Y, Gong C, Wang X, Qin M (2017) AR mutations in 28 patients with androgen insensitivity syndrome (Prader grade 0–3). Sci China Life Sci 60(7):700–706

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Zhonglin Cai and Weijie Chen have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China

    Zhonglin Cai, Jianzhong Zhang & Hongjun Li

  2. Department of Urology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai Traditional Chinese Medicine University, Shanghai, China

    Weijie Chen

Authors
  1. Zhonglin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weijie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianzhong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongjun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongjun Li.

Ethics declarations

Conflict of interest

Authors declare no conflicts of interest for this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, Z., Chen, W., Zhang, J. et al. Androgen receptor: what we know and what we expect in castration-resistant prostate cancer. Int Urol Nephrol 50, 1753–1764 (2018). https://doi.org/10.1007/s11255-018-1964-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-018-1964-0

Keywords

Search

Navigation