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Truncated Androgen Receptor Splice Variants in Prostate Cancer

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Prostate Cancer

Part of the book series: Protein Reviews ((PRON,volume 16))

Abstract

The androgen receptor (AR) is fundamental for the growth and survival of normal and malignant prostate cells. Therefore, androgen deprivation therapy remains the first-line treatment for disseminated disease; however, relapse and progression to a castration-resistant phenotype for which no durable treatment currently exists, is inevitable. Restored AR activity is fundamental in the progression to castration-resistant prostate cancer. Multiple mechanisms by which AR is reactivated under androgen-depleted conditions may be involved in the development of this lethal phenotype. Recent studies have identified alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the therapeutic target of androgen deprivation therapy. Many of these truncated AR variants function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as ligand-independent growth of prostate cancer cells. In this chapter, we will summarize the recent developments in the identification and characterization of AR splice variants in prostate cancer.

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References

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

    Article  PubMed  Google Scholar 

  2. Klein EA, Ciezki J, Kupelian PA, Mahadevan A (2009) Outcomes for intermediate risk ­prostate cancer: are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol 27(1):67–71

    Article  PubMed  Google Scholar 

  3. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, Middleton R, Sharp SA, Smith TJ, Talcott J, Taplin M, Vogelzang NJ, Wade JL, Bennett CL, Scher HI (2007) Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American society of clinical oncology practice guideline. J Clin Oncol 25(12):1596–1605

    Article  PubMed  CAS  Google Scholar 

  4. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ (1989) A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321(7):419–424

    Article  PubMed  CAS  Google Scholar 

  5. Denis LJ, Carneiro De Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M (1993) Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III eortc trial (30853). Urology 42(2):119–130

    Article  PubMed  CAS  Google Scholar 

  6. Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, Wilding G, Sears K, Culkin DJ, Thompson IM, Bueschen AJ, Lowe BA (1998) Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339(15):1036–1042

    Article  PubMed  CAS  Google Scholar 

  7. Leuprolide Study Group (1984) Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 311(20):1281–1286

    Article  Google Scholar 

  8. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Fig. WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol 26(7):1148–1159

    Article  PubMed  Google Scholar 

  9. Chang CS, Kokontis J, Liao ST (1988) Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci 85(19):7211–7215

    Article  PubMed  CAS  Google Scholar 

  10. Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, French FS (1989) 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 86(23):9534–9538

    Article  PubMed  CAS  Google Scholar 

  11. Gelmann EP (2002) Molecular biology of the androgen receptor. J Clin Oncol 20(13):3001–3015

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Ding D, Xu L, Menon M, Reddy GPV, Barrack ER (2004) Effect of a short CAG (glutamine) repeat on human androgen receptor function. Prostate 58(1):23–32

    Article  PubMed  CAS  Google Scholar 

  14. Ding D, Xu L, Menon M, Reddy GPV, Barrack ER (2005) Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action. Prostate 62(2):133–139

    Article  PubMed  CAS  Google Scholar 

  15. Ferro P, Catalano MG, Dell Eva R, Fortunati N, Pfeffer U (2002) The androgen receptor CAG repeat: a modifier of carcinogenesis? Mol Cell Endocrinol 193(1–2):109–120

    Article  PubMed  CAS  Google Scholar 

  16. Jenster G, van der Korput HAGM, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO (1991) Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 5(10):1396–1404

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  18. Callewaert L, Van Tilborgh N, Claessens F (2006) Interplay between two ­hormone-­independent activation domains in the androgen receptor. Cancer Res 66(1):543–553

    Article  PubMed  CAS  Google Scholar 

  19. Chamberlain NL, Whitacre DC, Miesfeld RL (1996) Delineation of two distinct type 1 activation functions in the androgen receptor amino-terminal domain. J Biol Chem 271(43):26772–26778

    Article  PubMed  CAS  Google Scholar 

  20. Dehm SM, Regan KM, Schmidt LJ, Tindall DJ (2007) Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells. Cancer Res 67(20):10067–10077

    Article  PubMed  CAS  Google Scholar 

  21. Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT (2004) Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci 101(14):4758–4763

    Article  PubMed  CAS  Google Scholar 

  22. Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT (2007) Nuclear receptor structure: implications for function. Annu Rev Physiol 69(1):201–220

    Article  PubMed  CAS  Google Scholar 

  23. Estebanez-Perpina E, Moore JMR, Mar E, Delgado-Rodrigues E, Nguyen P, Baxter JD, Buehrer BM, Webb P, Fletterick RJ, Guy RK (2005) The molecular mechanisms of coactivator utilization in ligand-dependent transactivation by the androgen receptor. J Biol Chem 280(9):8060–8068

    Article  PubMed  CAS  Google Scholar 

  24. Hur E, Pfaff SJ, Payne ES, Gron H, Buehrer BM, Fletterick RJ (2004) Recognition and accommodation at the androgen receptor coactivator binding interface. PLoS Biol 2(9):e274

    Article  PubMed  CAS  Google Scholar 

  25. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, Otto N, Joschko S, Scholz P, Wegg A, Basler S, Schäfer M, Egner U, Carrondo MA (2000) Structural evidence for ligand specificity in the binding domain of the human androgen receptor. J Biol Chem 275(34):26164–26171

    Article  PubMed  CAS  Google Scholar 

  26. Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE, Salvati ME, Krystek SR, Weinmann R, Einspahr HM (2001) 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 98(9):4904–4909

    Article  PubMed  CAS  Google Scholar 

  27. Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18(3):306–360

    Article  PubMed  CAS  Google Scholar 

  28. Smith DF, Toft DO (2008) Minireview: the intersection of steroid receptors with molecular chaperones: observations and questions. Mol Endocrinol 22(10):2229–2240

    Article  PubMed  CAS  Google Scholar 

  29. Zhou ZX, Sar M, Simental JA, Lane MV, Wilson EM (1994) A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences. J Biol Chem 269(18):13115–13123

    PubMed  CAS  Google Scholar 

  30. Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE (2008) Structural basis for the nuclear import of the human androgen receptor. J Cell Sci 121(7):957–968

    Article  PubMed  CAS  Google Scholar 

  31. Dehm SM, Tindall DJ (2006) Molecular regulation of androgen action in prostate cancer. J Cell Biochem 99(2):333–344

    Article  PubMed  CAS  Google Scholar 

  32. 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  PubMed  CAS  Google Scholar 

  33. He B, Gampe RT Jr, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, Wilson EM (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16(3):425–438

    Article  PubMed  CAS  Google Scholar 

  34. Hunter J (1840) Observations on certain parts of the animal economy. Haswell, Barrington and Haswell, Philadelphia, PA

    Google Scholar 

  35. Huggins C (1942) Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 115(6):1192–1200

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  37. Huggins C, Stevens RE, Hodges CV (1941) Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 43(2):209–223

    Article  CAS  Google Scholar 

  38. Moul JW (2009) Twenty years of controversy surrounding combined androgen blockade for advanced prostate cancer. Cancer 115(15):3376–3378

    Article  PubMed  Google Scholar 

  39. Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde DW, Scher HI (1999) Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst 91(21):1869–1876

    Article  PubMed  CAS  Google Scholar 

  40. Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10(2):440–448

    Article  PubMed  CAS  Google Scholar 

  41. Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH, van der Kwast TH (1994) Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol 144(4):735–746

    PubMed  CAS  Google Scholar 

  42. Sadi MV, Walsh PC, Barrack ER (1991) Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. Cancer 67(12):3057–3064

    Article  PubMed  CAS  Google Scholar 

  43. van der Kwast TH, Schalken J, de Winter JAR, van Vroonhoven JCC, Mulder E, Boersma W, Trapman J (1991) Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 48(2):189–193

    Article  PubMed  Google Scholar 

  44. Donovan MJ, Osman I, Khan FM, Vengrenyuk Y, Capodieci P, Koscuiszka M, Anand A, Cordon-Cardo C, Costa J, Scher HI (2010) Androgen receptor expression is associated with prostate cancer-specific survival in castrate patients with metastatic disease. BJU Int 105(4):462–467

    Article  PubMed  CAS  Google Scholar 

  45. Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, Scardino P, Reuter V, Gerald WL (2004) Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 164(1):217–227

    Article  PubMed  CAS  Google Scholar 

  46. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-­independent prostate cancer. Cancer Res 66(5):2815–2825

    Article  PubMed  CAS  Google Scholar 

  47. Taplin M-E, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, Balk SP (1995) Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332(21):1393–1398

    Article  PubMed  CAS  Google Scholar 

  48. Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T, Kallioniemi OP (1997) Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 57(2):314–319

    PubMed  CAS  Google Scholar 

  49. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi O-P (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9(4):401–406

    Article  PubMed  CAS  Google Scholar 

  50. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10(1):33–39

    Article  PubMed  CAS  Google Scholar 

  51. Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H (1993) Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol 7(12):1541–1550

    Article  PubMed  CAS  Google Scholar 

  52. Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, Balk SP (1999) Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 59(11):2511–2515

    PubMed  CAS  Google Scholar 

  53. Hara T, Miyazaki JI, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M (2003) Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 63(1):149–153

    PubMed  CAS  Google Scholar 

  54. Taplin M-E, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, Stadler W, Hayes DF, Kantoff PW, Vogelzang NJ, Small EJ (2003) Androgen receptor mutations in ­androgen-­independent prostate cancer: cancer and leukemia group B study 9663. J Clin Oncol 21(14):2673–2678

    Article  PubMed  CAS  Google Scholar 

  55. Yoshida T, Kinoshita H, Segawa T, Nakamura E, Inoue T, Shimizu Y, Kamoto T, Ogawa O (2005) Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res 65(21):9611–9616

    Article  PubMed  CAS  Google Scholar 

  56. Jiang Y, Palma JF, Agus DB, Wang Y, Gross ME (2010) Detection of androgen receptor mutations in circulating tumor cells in castration-resistant prostate cancer. Clin Chem 56(9):1492–1495

    Article  PubMed  Google Scholar 

  57. 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(11):4447–4454

    Article  PubMed  CAS  Google Scholar 

  58. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, Knudsen B, Hess DL, Nelson CC, Matsumoto AM, Bremner WJ, Gleave ME, Nelson PS (2007) Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res 67(10):5033–5041

    Article  PubMed  CAS  Google Scholar 

  59. Dufort I, Rheault P, Huang XF, Soucy P, Luu-The V (1999) Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase. Endocrinology 140(2):568–574

    Article  PubMed  CAS  Google Scholar 

  60. El-Alfy M, Luu-The V, Huang XF, Berger L, Labrie F, Pelletier G (1999) Localization of type 5 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinology 140(3):1481–1491

    Article  PubMed  CAS  Google Scholar 

  61. Lin HK, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM (1997) Expression and characterization of recombinant type 2 3α-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3α/17β-HSD activity and cellular distribution. Mol Endocrinol 11(13):1971–1984

    Article  PubMed  CAS  Google Scholar 

  62. Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K (2000) Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J 351(1):67–77

    Article  PubMed  CAS  Google Scholar 

  63. Ji Q, Chang L, VanDenBerg D, Stanczyk FZ, Stolz A (2003) Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism. Prostate 54(4):275–289

    Article  PubMed  CAS  Google Scholar 

  64. Rizner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM (2003) Human type 3 3α-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells. Endocrinology 144(7):2922–2932

    Article  PubMed  CAS  Google Scholar 

  65. Thomas LN, Douglas RC, Lazier CB, Too CKL, Rittmaster RS, Tindall DJ (2008) Type 1 and type 2 5α-reductase expression in the development and progression of prostate cancer. Eur Urol 53(2):244–252

    Article  PubMed  CAS  Google Scholar 

  66. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005

    Article  PubMed  Google Scholar 

  67. Ward RD, Weigel NL (2009) Steroid receptor phosphorylation: assigning function to site-­specific phosphorylation. Biofactors 35(6):528–536

    Article  PubMed  CAS  Google Scholar 

  68. Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, Nesheiwat I, Kong X, Melamed J, Handratta VD, Njar VCO, Brodie AMH, Yu L-R, Veenstra TD, Chen H, Qiu Y (2006) Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 10(4):309–319

    Article  PubMed  CAS  Google Scholar 

  69. Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE (2007) Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci 104(20):8438–8443

    Article  PubMed  CAS  Google Scholar 

  70. Popov VM, Wang C, Shirley LA, Rosenberg A, Li S, Nevalainen M, Fu M, Pestell RG (2007) The functional significance of nuclear receptor acetylation. Steroids 72(2):221–230

    Article  PubMed  CAS  Google Scholar 

  71. Dirac AMG, Bernards R (2010) The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Mol Cancer Res 8(6):844–854

    Article  PubMed  CAS  Google Scholar 

  72. Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F, Guo Z, Chen H, Li W, Chen H, Kong X, Melamed J, Fang S, Xiao Z, Veenstra TD, Qiu Y (2009) Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell 15(4):270–282

    Article  PubMed  CAS  Google Scholar 

  73. Kaikkonen S, Jääskeläinen T, Karvonen U, Rytinki MM, Makkonen H, Gioeli D, Paschal BM, Palvimo JJ (2009) SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol 23(3):292–307

    Article  PubMed  CAS  Google Scholar 

  74. Agoulnik IU, Weigel NL (2008) Androgen receptor coactivators and prostate cancer. Adv Exp Med Biol 617:245–255

    Article  PubMed  CAS  Google Scholar 

  75. Burd CJ, Morey LM, Knudsen KE (2006) Androgen receptor corepressors and prostate ­cancer. Endocr Relat Cancer 13(4):979–994

    Article  PubMed  CAS  Google Scholar 

  76. Brooke GN, Bevan CL (2009) The role of androgen receptor mutations in prostate cancer progression. Curr Genomics 10(1):18–25

    Article  PubMed  CAS  Google Scholar 

  77. Zoppi S, Wilson CM, Harbison MD, Griffin JE, Wilson JD, McPhaul MJ, Marcelli M (1993) Complete testicular feminization caused by an amino-terminal truncation of the androgen receptor with downstream initiation. J Clin Invest 91(3):1105–1112

    Article  PubMed  CAS  Google Scholar 

  78. Wilson CM, McPhaul MJ (1994) A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci 91(4):1234–1238

    Article  PubMed  CAS  Google Scholar 

  79. Ahrens-Fath I, Politz O, Geserick C, Haendler B (2005) Androgen receptor function is modulated by the tissue-specific AR45 variant. FEBS J 272(1):74–84

    Article  PubMed  CAS  Google Scholar 

  80. Wu Z-Y, Chen K, Haendler B, McDonald TV, Bian J-S (2008) Stimulation of N-terminal truncated isoform of androgen receptor stabilizes human ether-a-go-go-related gene-encoded potassium channel protein via activation of extracellular signal regulated kinase 1/2. Endocrinology 149(10):5061–5069

    Article  PubMed  CAS  Google Scholar 

  81. Wilson JD, Harrod MJ, Goldstein JL, Hemsell DL, MacDonald PC (1974) Familial incomplete male pseudohermaphroditism, type 1. N Engl J Med 290(20):1097–1103

    Article  PubMed  CAS  Google Scholar 

  82. Brinkmann AO (2001) Molecular basis of androgen insensitivity. Mol Cell Endocrinol 179(1–2):105–109

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  84. Gottlieb B, Beitel LK, Wu JH, Trifiro M (2004) The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 23(6):527–533

    Article  PubMed  CAS  Google Scholar 

  85. Ris-Stalpers C, Kuiper GG, Faber PW, Schweikert HU, van Rooij HC, Zegers ND, Hodgins MB, Degenhart HJ, Trapman J, Brinkmann AO (1990) Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity. Proc Natl Acad Sci 87(20):7866–7870

    Article  PubMed  CAS  Google Scholar 

  86. Hellwinkel OJ-C, Bull K, Holterhus P-M, Homburg N, Struve D, Hiort O (1999) Complete androgen insensitivity caused by a splice donor site mutation in intron 2 of the human androgen receptor gene resulting in an exon 2-lacking transcript with premature stop-codon and reduced expression. J Steroid Biochem Mol Biol 68(1–2):1–9

    Article  PubMed  CAS  Google Scholar 

  87. Lim J, Ghadessy FJ, Yong EL (1997) A novel splice site mutation in the androgen receptor gene results in exon skipping and a non-functional truncated protein. Mol Cell Endocrinol 131(2):205–210

    Article  PubMed  CAS  Google Scholar 

  88. Ris-Stalpers C, Verleun-Mooijman MC, de Blaeij TJ, Degenhart HJ, Trapman J, Brinkmann AO (1994) Differential splicing of human androgen receptor pre-mRNA in X-linked Reifenstein syndrome, because of a deletion involving a putative branch site. Am J Hum Genet 54(4):609–617

    PubMed  CAS  Google Scholar 

  89. Bruggenwirth HT, Boehmer ALM, Ramnarain S, Verleun-Mooijman MCT, Satijn DPE, Trapman J, Grootegoed JA, Brinkmann AO (1997) Molecular analysis of the androgen-­receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation. Am J Hum Genet 61(5):1067–1077

    Article  PubMed  CAS  Google Scholar 

  90. Sammarco I, Grimaldi P, Rossi P, Cappa M, Moretti C, Frajese G, Geremia R (2000) Novel point mutation in the splice donor site of exon-intron junction 6 of the androgen receptor gene in a patient with partial androgen insensitivity syndrome. J Clin Endocrinol Metab 85(9):3256–3261

    Article  PubMed  CAS  Google Scholar 

  91. Hellwinkel OJ-C, Holterhus P-M, Struve D, Marschke C, Homburg N, Hiort O (2001) A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants. J Clin Endocrinol Metab 86(6):2569–2575

    Article  PubMed  CAS  Google Scholar 

  92. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB (2011) Resistance to CYP17A1 inhibition with abiraterone in castration-­resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17(18):5913–5925

    Article  PubMed  CAS  Google Scholar 

  93. Scher HI, Beer TM, Higano CS, Anand A, Taplin M-E, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375(9724):1437–1446

    Article  PubMed  CAS  Google Scholar 

  94. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928):787–790

    Article  PubMed  CAS  Google Scholar 

  95. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72(6):1494–1503

    Article  PubMed  CAS  Google Scholar 

  96. Tepper CG, Boucher DL, Ryan PE, Ma A-H, Xia L, Lee L-F, Pretlow TG, Kung H-J (2002) Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Cancer Res 62(22):6606–6614

    PubMed  CAS  Google Scholar 

  97. Wainstein MA, He F, Robinson D, Kung H-J, Schwartz S, Giaconia JM, Edgehouse NL, Pretlow TP, Bodner DR, Kursh ED, Resnick MI, Seftel A, Pretlow TG (1994) CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res 54(23):6049–6052

    PubMed  CAS  Google Scholar 

  98. Nagabhushan M, Miller CM, Pretlow TP, Giaconia JM, Edgehouse NL, Schwartz S, Kung H-J, de Vere White RW, Gumerlock PH, Resnick MI, Amini SB, Pretlow TG (1996) CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Cancer Res 56(13):3042–3046

    PubMed  CAS  Google Scholar 

  99. Sramkoski RM, Pretlow TG, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D, Jacobberger JW (1999) A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim 35(7):403–409

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  101. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung H-J, Brodie AMH, 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(6):2305–2313

    Article  PubMed  CAS  Google Scholar 

  102. 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  PubMed  CAS  Google Scholar 

  103. Hu R, Isaacs WB, Luo J (2011) A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate 71(15):1656–1667

    Article  PubMed  CAS  Google Scholar 

  104. Marcias G, Erdmann E, Lapouge G, Siebert C, Barthelemy P, Duclos B, Bergerat J-P, Ceraline J, Kurtz J-E (2010) Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line. Hum Mutat 31(1):74–80

    Article  PubMed  CAS  Google Scholar 

  105. Sun S, Sprenger CCT, 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(8):2715–2730

    Article  PubMed  CAS  Google Scholar 

  106. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers CL (2010) Constitutively active androgen receptor splice variants expressed in castration-­resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci 107(39):16759–16765

    Article  PubMed  CAS  Google Scholar 

  107. Yang X, Guo Z, Sun F, Li W, Alfano A, Shimelis H, Chen M, Brodie AMH, Chen H, Xiao Z, Veenstra TD, Qiu Y (2011) Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. J Biol Chem 286(41):36152–36160

    Article  PubMed  CAS  Google Scholar 

  108. Jagla M, Feve M, Kessler P, Lapouge G, Erdmann E, Serra S, Bergerat J-P, Ceraline J (2007) A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions. Endocrinology 148(9):4334–4343

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  110. Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM (2011) Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res 71(6):2108–2117

    Article  PubMed  CAS  Google Scholar 

  111. Korenchuk S, Lehr JE, MClean L, Lee YG, Whitney S, Vessella R, Lin DL, Pienta KJ (2001) VCaP, a cell-based model system of human prostate cancer. In Vivo 15(2):163–168

    PubMed  CAS  Google Scholar 

  112. Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, Thomas GV, Sawyers CL (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4(3):223–238

    Article  PubMed  CAS  Google Scholar 

  113. Watson PA, Ellwood-Yen K, King JC, Wongvipat J, LeBeau MM, Sawyers CL (2005) Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line. Cancer Res 65(24):11565–11571

    Article  PubMed  CAS  Google Scholar 

  114. Ceraline J, Cruchant MD, Erdmann E, Erbs P, Kurtz J-E, Duclos B, Jacqmin D, Chopin D, Bergerat J-P (2004) Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. Int J Cancer 108(1):152–157

    Article  PubMed  CAS  Google Scholar 

  115. Lapouge G, Erdmann E, Marcias G, Jagla M, Monge A, Kessler P, Serra S, Lang H, Jacqmin D, Bergerat J-P, Ceraline J (2007) Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation—a new paradigm for cooperation among prostate tumor cells. Int J Cancer 121(6):1238–1244

    Article  PubMed  CAS  Google Scholar 

  116. Zhang X, Morrissey C, Sun S, Ketchandji M, Nelson PS, True LD, Vakar-Lopez F, Vessella RL, Plymate SR (2011) Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS One 6(11):e27970

    Article  PubMed  CAS  Google Scholar 

  117. 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  PubMed  CAS  Google Scholar 

  118. Mashima T, Okabe S, Seimiya H (2010) Pharmacological targeting of constitutively active truncated androgen receptor by nigericin and suppression of hormone-refractory prostate cancer cell growth. Mol Pharmacol 78(5):846–854

    Article  PubMed  CAS  Google Scholar 

  119. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H, Lupien M, Wu T, Regan MM, Meyer CA, Carroll JS, Manrai AK, Janne OA, Balk SP, Mehra R, Han B, Chinnaiyan AM, Rubin MA, True L, Fiorentino M, Fiore C, Loda M, Kantoff PW, Liu XS, Brown M (2009) Androgen receptor regulates a distinct transcription program in androgen-­independent prostate cancer. Cell 138(2):245–256

    Article  PubMed  CAS  Google Scholar 

  120. Hornberg 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  CAS  Google Scholar 

  121. Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, Edwards J, Isaacs W, Nelson PS, Bluemn E, Plymate SR, Luo J (2012) Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-­resistant prostate cancer. Cancer Res 72(14):3457–3462

    Article  PubMed  CAS  Google Scholar 

  122. Chen H, Libertini SJ, Wang Y, Kung H-J, Ghosh P, Mudryj M (2010) ERK regulates calpain 2-induced androgen receptor proteolysis in CWR22 relapsed prostate tumor cell lines. J Biol Chem 285(4):2368–2374

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  124. Sivanandam A, Murthy S, Chinnakannu K, Bai VU, Kim S-H, Barrack ER, Menon M, Reddy GP-V (2011) Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells. J Cell Physiol 226(7):1889–1896

    Article  PubMed  CAS  Google Scholar 

  125. Li Y, Hwang TH, Oseth LA, Hauge A, Vessella RL, Schmechel SC, Hirsch B, Beckman KB, Silverstein KA, Dehm SM (2012) AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene 31(45):4759–4767

    Article  PubMed  CAS  Google Scholar 

  126. Quayle SN, Mawji NR, Wang J, Sadar MD (2007) Androgen receptor decoy molecules block the growth of prostate cancer. Proc Natl Acad Sci 104(4):1331–1336

    Article  PubMed  CAS  Google Scholar 

  127. Sadar MD (2011) Small molecule inhibitors targeting the “Achilles’ heel” of androgen receptor activity. Cancer Res 71(4):1208–1213

    Article  PubMed  CAS  Google Scholar 

  128. Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung J-K, Watt K, Tam T, Yang YC, Banuelos CA, Williams DE, McEwan IJ, Wang Y, Sadar MD (2010) Regression of castrate-­recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17(6):535–546

    Article  PubMed  CAS  Google Scholar 

  129. Sadar MD (2012) Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer. World J Urol 30(3):311–318

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported by the NIH (CA125747, CA091956 and CA121277) and the T.J. Martell Foundation (DJT). PEL is supported by a Fulbright Scholarship and the Postgraduate Traveling Scholarship in Medicine from Trinity College, Dublin.

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  1. Department of Urology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA

    Peter E. Lonergan M.D., MRCSI

  2. Department of Urology, Biochemistry and Molecular Biology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA

    Donald J. Tindall Ph.D.

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  1. Peter E. Lonergan M.D., MRCSI
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Correspondence to Donald J. Tindall Ph.D. .

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  1. , Depts of Urology, and, Mayo Clinic College of Medicine, 200 1st Street SW., Rochester, 55905, Minnesota, USA

    Donald J. Tindall

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Lonergan, P.E., Tindall, D.J. (2013). Truncated Androgen Receptor Splice Variants in Prostate Cancer. In: Tindall, D. (eds) Prostate Cancer. Protein Reviews, vol 16. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6828-8_13

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