Molecular aspects of androgenic signaling and possible targets for therapeutic intervention in prostate cancer

Steroids

Volumn 78, Issue 9, 2013, Pages 851-859

  Culig, Zoran ^a   Santer, Frédéric R ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

Author keywords

Androgen receptor; Coactivators; Intracrine synthesis; MiRNA; Prostate cancer; Truncated androgen receptor

Indexed keywords

3(OR 17)BETA HYDROXYSTEROID DEHYDROGENASE; ABIRATERONE ACETATE; ANDROGEN RECEPTOR; ANDROSTANEDIOL; ANDROSTANOLONE; ANTINEOPLASTIC AGENT; BETA CATENIN; BICALUTAMIDE; CARBIDOPA; CYCLIN D1; CYCLIN D2; CYCLIN DEPENDENT KINASE 6; DOCETAXEL; FILAMIN A; FLUTAMIDE; HISTONE H3; HYDROXYFLUTAMIDE; INTERLEUKIN 6; KETOCONAZOLE; LUTEINIZING HORMONE; MICRORNA; OGX 427; PLACEBO; PREDNISONE; PROSTATE SPECIFIC ANTIGEN; SOMATOMEDIN C; SURVIVIN; TESTOSTERONE; TRANSCRIPTION FACTOR RELA; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANDROGEN BLOOD LEVEL; ANDROGEN SYNTHESIS; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER RESISTANCE; CASTRATION RESISTANT PROSTATE CANCER; CELL CYCLE PROGRESSION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); DNA DAMAGE; DRUG DEVELOPMENT; DRUG POTENCY; DRUG WITHDRAWAL; ENZYME ACTIVITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LUTEINIZING HORMONE BLOOD LEVEL; NONHUMAN; OVERALL SURVIVAL; PROSTATE CANCER; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TESTOSTERONE BLOOD LEVEL; UPREGULATION;

EID: 84885015108     PISSN: 0039128X     EISSN: 18785867     Source Type: Journal    
DOI: 10.1016/j.steroids.2013.04.012     Document Type: Review

References (115)

1. Van der Kwast TH, Schalken J, Ruizeveld de Winter JA, Van Vroonhoven CC, Mulder E, Boersma W, et al. Androgen receptors in endocrine-therapyresistant human prostate cancer. Int J Cancer 1991;48:189-93.
2. Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res 1995;55:3068-72.
3. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995;9:401-6.
4. Kokontis J, Takakura K, Hay N, Liao S. Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res 1994;54:1566-73. (Pubitemid 24106424)
5. Dai J, Shen R, Sumitomo M, Stahl R, Navarro D, Gershengorn MC, et al. Synergistic activation of the androgen receptor by bombesin and low-dose androgen. Clin Cancer Res 2002;8:2399-405. (Pubitemid 34753615)
6. Wright ME, Tsai M-J, Aebersold R. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrinol 2003;17:1726-37. (Pubitemid 37072290)
7. Kim D, Gregory CW, French FS, Smith GJ, Mohler JL. Androgen receptor expression and cellular proliferation during transition from androgendependent to recurrent growth after castration in the CWR22 prostate cancer xenograft. Am J Pathol 2002;160:219-26. (Pubitemid 34052282)
8. Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res 2002;62:1008-13. (Pubitemid 34160279)
9. Kinoshita H, Shi Y, Sandefur C, Meisner LF, Chang C, Choon A, et al. Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer. Cancer Res 2000;60:3623-30. (Pubitemid 30482185)
10. Bao B-Y, Hu Y-C, Ting H-J, Lee Y-F. Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells. Oncogene 2004;23:3350-60. (Pubitemid 38669824)
11. Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004;164:217-27. (Pubitemid 38364606)
12. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castrationresistant prostate cancer. Cancer Res 2007;67:5033-41. (Pubitemid 46910214)
13. Mohler JL, Gregory CW, Ford 3rd OH, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10:440-8. (Pubitemid 38173980)
14. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 2005;11:4653-7. (Pubitemid 41557182)
15. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008;68:4447-54.
16. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15.
17. Dillard PR, Lin M-F, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol 2008;295:115-20.
18. Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res 2011;71:1486-96.
19. Reid AH, Attard G, Barrie E, De Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol 2008;5:610-20.
20. Li R, Evaul K, Sharma KK, Chang K-H, Yoshimoto J, Liu J, et al. Abiraterone inhibits 3b-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer. Clin Cancer Res 2012;18:3571-9.
21. Soifer HS, Souleimanian N, Wu S, Voskresenskiy AM, Collak FK, Cinar B, et al. Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells. J Biol Chem 2012;287:3777-87.
22. Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res 2012;72:2176-82.
23. De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005.
24. Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis CJ, De Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48.
25. Chun JY, Nadiminty N, Dutt S, Lou W, Yang JC, Kung H-J, et al. Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clin Cancer Res 2009;15:4815-22.
26. Pinski J, Xiong S, Wang Q, Stanczyk F, Hawes D, Liu SV. Effect of luteinizing hormone on the steroidogenic pathway in prostate cancer. Prostate 2011;71:892-8.
27. Lubik AA, Gunter JH, Hendy SC, Locke JA, Adomat HH, Thompson V, et al. Insulin increases de novo steroidogenesis in prostate cancer cells. Cancer Res 2011;71:5754-64.
28. Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci USA 1996;93:5517-21.
29. Alen P, Claessens F, Schoenmakers E, Swinnen JV, Verhoeven G, Rombauts W, et al. Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform. Mol Endocrinol 1999;13:117-28. (Pubitemid 29022284)
30. Peng Y, Li CX, Chen F, Wang Z, Ligr M, Melamed J, et al. Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor coactivator ARA70. Am J Pathol 2008;172:225-35. (Pubitemid 351186383)
31. Ligr M, Li Y, Zou X, Daniels G, Melamed J, Peng Y, et al. Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer. Am J Pathol 2010;176:1891-900.
32. Peng Y, Chen F, Melamed J, Chiriboga L, Wei J, Kong X, et al. Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer. Proc Natl Acad Sci USA 2008;105:5236-41. (Pubitemid 351738540)
33. Gounari F, Signoretti S, Bronson R, Klein L, Sellers WR, Kum J, et al. Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. Oncogene 2002;21:4099-107. (Pubitemid 34712877)
34. Verras M, Sun Z. Beta-catenin is involved in insulin-like growth factor 1-mediated transactivation of the androgen receptor. Mol Endocrinol 2005;19:391-8. (Pubitemid 40223463)
35. Wang G, Wang J, Sadar MD. Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res 2008;68:9918-27.
36. Debes JD, Sebo TJ, Lohse CM, Murphy LM, Haugen DAL, Tindall DJ. P300 in prostate cancer proliferation and progression. Cancer Res 2003;63:7638-40. (Pubitemid 37466688)
37. Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, et al. Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 2009;16:155-69.
38. Debes JD, Comuzzi B, Schmidt LJ, Dehm SM, Culig Z, Tindall DJ. P300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res 2005;65:5965-73. (Pubitemid 40911204)
39. Gong J, Zhu J, Goodman Jr OB, Pestell RG, Schlegel PN, Nanus DM, et al. Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells. Oncogene 2006;25:2011-21.
40. Miyajima N, Maruyama S, Bohgaki M, Kano S, Shigemura M, Shinohara N, et al. TRIM68 regulates ligand-dependent transcription of androgen receptor in prostate cancer cells. Cancer Res 2008;68:3486-94.
41. Tan S-H, Dagvadorj A, Shen F, Gu L, Liao Z, Abdulghani J, et al. Transcription factor Stat5 synergizes with androgen receptor in prostate cancer cells. Cancer Res 2008;68:236-48. (Pubitemid 351380125)
42. Comuzzi B, Lambrinidis L, Rogatsch H, Godoy-Tundidor S, Knezevic N, Krhen I, et al. The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen-and anti-androgen-induced androgen receptor function. Am J Pathol 2003;162:233-41. (Pubitemid 36042005)
43. Comuzzi B, Nemes C, Schmidt S, Jasarevic Z, Lodde M, Pycha A, et al. The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer. J Pathol 2004;204:159-66. (Pubitemid 39335289)
44. Heemers HV, Sebo TJ, Debes JD, Regan KM, Raclaw KA, Murphy LM, et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res 2007;67:3422-30. (Pubitemid 46724883)
45. Nishimura K, Ting H-J, Harada Y, Tokizane T, Nonomura N, Kang H-Y, et al. Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator. Cancer Res 2003;63:4888-94. (Pubitemid 37022622)
46. Zhang M, Latham DE, Delaney MA, Chakravarti A. Survivin mediates resistance to antiandrogen therapy in prostate cancer. Oncogene 2005;24:2474-82. (Pubitemid 40593038)
47. Wang Y, Kreisberg JI, Bedolla RG, Mikhailova M. DeVere White RW, Ghosh PM. A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells. Oncogene 2007;26:6061-70.
48. Mäki HE, Saramäki OR, Shatkina L, Martikainen PM, Tammela TLJ, Van Weerden WM, et al. Overexpression and gene amplification of BAG-1L in hormone-refractory prostate cancer. J Pathol 2007;212:395-401. (Pubitemid 47099016)
49. Tillman JE, Yuan J, Gu G, Fazli L, Ghosh R, Flynt AS, et al. DJ-1 binds androgen receptor directly and mediates its activity in hormonally treated prostate cancer cells. Cancer Res 2007;67:4630-7. (Pubitemid 46910167)
50. Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003;63:149-53. (Pubitemid 36070433)
51. Santer FR, Höschele PPS, Oh SJ, Erb HHH, Bouchal J, Cavarretta IT, et al. Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol Cancer Ther 2011;10:1644-55.
52. Ianculescu I, Wu D-Y, Siegmund KD, Stallcup MR. Selective roles for cAMP response element-binding protein binding protein and p300 protein as coregulators for androgen-regulated gene expression in advanced prostate cancer cells. J Biol Chem 2012;287:4000-13.
53. Wang Z, Wang Z, Guo J, Li Y, Bavarva JH, Qian C, et al. Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis. Proc Natl Acad Sci USA 2012;109:3053-8.
54. Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady ME, Cook S, et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 2003;22:2466-77. (Pubitemid 36560730)
55. Coffey K, Blackburn TJ, Cook S, Golding BT, Griffin RJ, Hardcastle IR, et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer. PLoS ONE 2012;7:e45539.
56. Bonaccorsi L, Carloni V, Muratori M, Formigli L, Zecchi S, Forti G, et al. EGF receptor (EGFR) signaling promoting invasion is disrupted in androgensensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR). Int J Cancer 2004;112:78-86. (Pubitemid 39249494)
57. Gregory CW, Fei X, Ponguta LA, He B, Bill HM, French FS, et al. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem 2004;279:7119-30. (Pubitemid 38248859)
58. Agoulnik IU, Vaid A, Nakka M, Alvarado M, Bingman 3rd WE, Erdem H, 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;66:10594-602. (Pubitemid 44799783)
59. Feng S, Tang Q, Sun M, Chun JY, Evans CP, Gao AC. Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2. Mol Cancer Ther 2009;8:665-71.
60. Steiner H, Godoy-Tundidor S, Rogatsch H, Berger AP, Fuchs D, Comuzzi B, et al. Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. Am J Pathol 2003;162:655-63. (Pubitemid 36267872)
61. Thomas C, Wafa LA, Lamoureux F, Cheng H, Fazli L, Gleave ME, et al. Carbidopa enhances antitumoral activity of bicalutamide on the androgen receptor-axis in castration-resistant prostate tumors. Prostate 2012;72:875-85.
62. Mäki HE, Waltering KK, Wallén MJ, Martikainen PM, Tammela TLJ, Van Weerden WM, et al. Screening of genetic and expression alterations of SRC1 gene in prostate cancer. Prostate 2006;66:1391-8. (Pubitemid 44350364)
63. Zhou H-J, Yan J, Luo W, Ayala G, Lin S-H, Erdem H, et al. SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res 2005;65:7976-83. (Pubitemid 41297277)
64. Axlund SD, Lambert JR, Nordeen SK. HOXC8 inhibits androgen receptor signaling in human prostate cancer cells by inhibiting SRC-3 recruitment to direct androgen target genes. Mol Cancer Res 2010;8:1643-55.
65. Lyons LS, Burnstein KL. Vav3, a Rho GTPase guanine nucleotide exchange factor, increases during progression to androgen independence in prostate cancer cells and potentiates androgen receptor transcriptional activity. Mol Endocrinol 2006;20:1061-72.
66. Dong Z, Liu Y, Lu S, Wang A, Lee K, Wang L-H, et al. Vav3 oncogene is overexpressed and regulates cell growth and androgen receptor activity in human prostate cancer. Mol Endocrinol 2006;20:2315-25. (Pubitemid 44496404)
67. Liu Y, Mo JQ, Hu Q, Boivin G, Levin L, Lu S, et al. Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. Cancer Res 2008;68:6396-406.
68. Kaulfuss S, Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Neesen J, et al. Leupaxin, a novel coactivator of the androgen receptor, is expressed in prostate cancer and plays a role in adhesion and invasion of prostate carcinoma cells. Mol Endocrinol 2008;22:1606-21. (Pubitemid 351920394)
69. Clark EL, Coulson A, Dalgliesh C, Rajan P, Nicol SM, Fleming S, et al. The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Res 2008;68:7938-46.
70. Wissmann M, Yin N, Müller JM, Greschik H, Fodor BD, Jenuwein T, et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 2007;9:347-53.
71. Logan IR, Gaughan L, McCracken SRC, Sapountzi V, Leung HY, Robson CN. Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer. Mol Cell Biol 2006;26:6502-10. (Pubitemid 44277889)
72. Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P, et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res 2007;67:10455-65. (Pubitemid 350070821)
73. Nwachukwu JC, Mita P, Ruoff R, Ha S, Wang Q, Huang SJ, et al. Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells. Cancer Res 2009;69:3140-7.
74. Heitzer MD, DeFranco DB. Mechanism of action of Hic-5/androgen receptor activator 55, a LIM domain-containing nuclear receptor coactivator. Mol Endocrinol 2006;20:56-64. (Pubitemid 43011670)
75. Heemers HV, Regan KM, Schmidt LJ, Anderson SK, Ballman KV, Tindall DJ. Androgen modulation of coregulator expression in prostate cancer cells. Mol Endocrinol 2009;23:572-83.
76. Heemers HV, Schmidt LJ, Kidd E, Raclaw KA, Regan KM, Tindall DJ. Differential regulation of steroid nuclear receptor coregulator expression between normal and neoplastic prostate epithelial cells. Prostate 2010;70:959-70.
77. Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, et al. A central domain of cyclin D1 mediates nuclear receptor corepressor activity. Oncogene 2005;24:431-44. (Pubitemid 40188591)
78. Lim JTE, Mansukhani M, Weinstein IB. Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Proc Natl Acad Sci USA 2005;102:5156-61.
79. Burd CJ, Petre CE, Morey LM, Wang Y, Revelo MP, Haiman CA, et al. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci USA 2006;103:2190-5. (Pubitemid 43271645)
80. Olshavsky NA, Groh EM, Comstock CES, Morey LM, Wang Y, Revelo MP, et al. Cyclin D3 action in androgen receptor regulation and prostate cancer. Oncogene 2008;27:3111-21. (Pubitemid 351693176)
81. Gamble SC, Chotai D, Odontiadis M, Dart DA, Brooke GN, Powell SM, et al. Prohibitin, a protein downregulated by androgens, represses androgen receptor activity. Oncogene 2007;26:1757-68. (Pubitemid 46426196)
82. Dart DA, Brooke GN, Sita-Lumsden A, Waxman J, Bevan CL. Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens. Oncogene 2012;31:4588-98.
83. Fletcher CE, Dart DA, Sita-Lumsden A, Cheng H, Rennie PS, Bevan CL. Androgen-regulated processing of the oncomir miR-27a, which targets prohibitin in prostate cancer. Hum Mol Genet 2012;21:3112-27.
84. Moehren U, Papaioannou M, Reeb CA, Hong W, Baniahmad A. Alien interacts with the human androgen receptor and inhibits prostate cancer cell growth. Mol Endocrinol 2007;21:1039-48. (Pubitemid 46984757)
85. 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;67:8388-95. (Pubitemid 47395178)
86. Lakshmikanthan V, Zou L, Kim JI, Michal A, Nie Z, Messias NC, et al. Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer. Proc Natl Acad Sci USA 2009;106:9379-84.
87. Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, Latonen LM, et al. Androgen regulation of micro-RNAs in prostate cancer. Prostate 2011;71:604-14.
88. Östling P, Leivonen S-K, Aakula A, Kohonen P, Mäkelä R, Hagman Z, et al. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res 2011;71:1956-67.
89. Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, et al. MiR-21: an androgen receptor-regulated microRNA that promotes hormonedependent and hormone-independent prostate cancer growth. Cancer Res 2009;69:7165-9.
90. Jalava SE, Urbanucci A, Latonen L, Waltering KK, Sahu B, Jänne OA, et al. Androgen-regulated miR-32 targets BTG2 and is overexpressed in castrationresistant prostate cancer. Oncogene 2012;31:4460-71.
91. Rokhlin OW, Scheinker VS, Taghiyev AF, Bumcrot D, Glover RA, Cohen MB. MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer. Cancer Biol Ther 2008;7:1288-96.
92. Sun T, Wang Q, Balk S, Brown M, Lee G-SM, Kantoff P. The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res 2009;69:3356-63.
93. Spahn M, Kneitz S, Scholz C-J, Stenger N, Rüdiger T, Ströbel P, et al. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer 2010;127:394-403.
94. Epis MR, Giles KM, Barker A, Kendrick TS, Leedman PJ. MiR-331-3p regulates ERBB-2 expression and androgen receptor signaling in prostate cancer. J Biol Chem 2009;284:24696-704.
95. Sikand K, Slaibi JE, Singh R, Slane SD, Shukla GC. MiR 488/ inhibits androgen receptor expression in prostate carcinoma cells. Int J Cancer 2011;129:810-9.
96. Nadiminty N, Tummala R, Lou W, Zhu Y, Zhang J, Chen X, et al. MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells. J Biol Chem 2012;287:1527-37.
97. Boll K, Reiche K, Kasack K, Mörbt N, Kretzschmar AK, Tomm JM, et al. MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene 2013;32:277-85.
98. Shi X-B, Xue L, Ma A-H, Tepper CG, Gandour-Edwards R, Kung H-J, et al. Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells. Oncogene 2012.
99. Lapouge G, Erdmann E, Marcias G, Jagla M, Monge A, Kessler P, et al. 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 2007;121:1238-44. (Pubitemid 47293790)
100. 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;68:5469-77.
101. Libertini SJ, Tepper CG, Rodriguez V, Asmuth DM, Kung H-J, Mudryj M. Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res 2007;67:9001-5. (Pubitemid 47535881)
102. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer 2011;18:R183-96.
103. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al. Ligandindependent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009;69:16-22.
104. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 2009;69:2305-13.
105. Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM. Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cellbased model of prostate cancer progression. Cancer Res 2011;71:2108-17.
106. Chan SC, Li Y, Dehm SM. 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 2012;287:19736-49.
107. Marcias G, Erdmann E, Lapouge G, Siebert C, Barthélémy P, Duclos B, et al. 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 2010;31:74-80.
108. Sun S, Sprenger CCT, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 2010;120:2715-30.
109. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA 2010;107:16759-65.
110. Li Y, Chan C, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castrationresistant prostate cancer cell lines. Cancer Res 2013:483-9.
111. Hörnberg E, Ylitalo EB, Crnalic S, Antti H, Stattin P, Widmark A, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 2011;6:e19059.
112. Zhang X, Morrissey C, Sun S, Ketchandji M, Nelson PS, True LD, et al. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS ONE 2011;6:e27970.
113. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, et al. Resistance to CYP17A1 inhibition with abiraterone in castrationresistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011;17:5913-25.
114. Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res 2011;71:6503-13.
115. Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent fulllength androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 2012;72:3457-62.