Hormones and Cancer

, Volume 5, Issue 5, pp 265–273 | Cite as

Androgen Receptor Splice Variants in the Era of Enzalutamide and Abiraterone

  • Mary Nakazawa
  • Emmanuel S. Antonarakis
  • Jun LuoEmail author


The FDA approvals of enzalutamide and abiraterone have rapidly changed the clinical landscape of prostate cancer treatment. Both drugs were designed to further suppress androgen receptor (AR) signaling, which is restored following first-line androgen deprivation therapies. Resistance to enzalutamide and abiraterone, however, is again marked by a return of AR signaling, indicating a remarkable “addiction” of prostate cancer cells to the AR pathway. Several mechanisms of castration resistance have been uncovered in the past decades, featuring a wide spectrum of molecular alterations that may explain sustained AR signaling in castration-resistant prostate cancers (CRPC). Among these, the androgen receptor splice variants (AR-Vs), particularly variant 7 (AR-V7), have been implicated in resistance to enzalutamide and abiraterone in preclinical studies, and they cannot be targeted by currently available AR-directed drugs. Drug development for AR-V-associated CRPC may therefore be necessary to augment the preexisting treatment repertoire. In this mini-review, we will discuss general mechanisms of resistance to AR-directed therapies, with a focus on the role of androgen receptor splice variants in the new era of treating advanced prostate cancer with enzalutamide and abiraterone.


Androgen Androgen Receptor Glucocorticoid Receptor Androgen Deprivation Therapy Abiraterone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Andersen RJ, Mawji NR, Wang J et al (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):535–546PubMedCrossRefGoogle Scholar
  2. 2.
    Aparicio A, Tzelepi V, Araujo JC et al (2011) Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient’s tumor: Morphological, immunohistochemical, and gene expression profiles. Prostate 71(8):846–856PubMedCrossRefGoogle Scholar
  3. 3.
    Arora VK, Schenkein E, Murali R et al (2013) Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155(6):1309–1322PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Aryee MJ, Liu W, Engelmann JC et al (2013) DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci Transl Med 5(169):169ra110CrossRefGoogle Scholar
  5. 5.
    Attard G, Reid AH, Yap TA et al (2008) Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 26(28):4563–4571PubMedCrossRefGoogle Scholar
  6. 6.
    Balbas MD, Evans MJ, Hosfield DJ et al (2013) Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife 2:e00499PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Beer TM, Armstrong AJ, Rathkopf DE, et al (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J MedGoogle Scholar
  8. 8.
    Beltran H, Beer TM, Carducci MA et al (2011) New therapies for castration-resistant prostate cancer: efficacy and safety. Eur Urol 60(2):279–290PubMedCrossRefGoogle Scholar
  9. 9.
    Beltran H, Tagawa ST, Park K et al (2012) Challenges in recognizing treatment-related neuroendocrine prostate cancer. J Clin Oncol 30(36):e386–e389PubMedCrossRefGoogle Scholar
  10. 10.
    Berruti A, Mosca A, Porpiglia F et al (2007) Chromogranin A expression in patients with hormone naive prostate cancer predicts the development of hormone refractory disease. J Urol 178(3 Pt 1):838–843, quiz 1129PubMedCrossRefGoogle Scholar
  11. 11.
    Bohrer LR, Liu P, Zhong J et al (2013) FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. Prostate 73(10):1017–1027PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bolton EC, So AY, Chaivorapol C et al (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21(16):2005–2017PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Bonkhoff H, Fixemer T, Hunsicker I et al (2001) Progesterone receptor expression in human prostate cancer: correlation with tumor progression. Prostate 48(4):285–291PubMedCrossRefGoogle Scholar
  14. 14.
    Bubendorf L, Kononen J, Koivisto P et al (1999) Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res 59(4):803–806PubMedGoogle Scholar
  15. 15.
    Cai C, He HH, Chen S, et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20(4):457–471Google Scholar
  16. 16.
    Cao B, Qi Y, Zhang G et al (2014) Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5(6):1646–1656PubMedGoogle Scholar
  17. 17.
    Carver BS, Chapinski C, Wongvipat J et al (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19(5):575–586PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Chang K-H, Li R, Kuri B et al (2013) A gain-of-function mutation in DHT synthesis in castration-resistant prostate Cancer. Cell 154(5):1074–1084PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Chang K-H, Li R, Papari-Zareei M et al (2011) Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci 108(33):13728–13733PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Chen CD, Welsbie DS, Tran C et al (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10(1):33–39PubMedCrossRefGoogle Scholar
  21. 21.
    Chen Y, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8(4):440–448PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Clegg NJ, Wongvipat J, Tran C, et al (2012) ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer ResGoogle Scholar
  23. 23.
    Culig Z, Hobisch A, Cronauer MV et al (1994) Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 54(20):5474–5478PubMedGoogle Scholar
  24. 24.
    de Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Dehm SM, Tindall DJ (2011) Alternatively spliced androgen receptor variants. Endocr Relat Cancer 18(5):R183–R196PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Dehm SM, Schmidt LJ, Heemers HV et al (2008) Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 68(13):5469–5477PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Di Lorenzo G, Buonerba C, Autorino R et al (2010) Castration-resistant prostate cancer. Drugs 70(8):983–1000PubMedCrossRefGoogle Scholar
  28. 28.
    Epstein JI, Amin MB, Beltran H et al (2014) Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol 38(6):756–767PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ferraldeschi R, Welti J, Luo J, et al (2014) Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. OncogeneGoogle Scholar
  30. 30.
    Gregory CW, He B, Johnson RT et al (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61(11):4315–4319PubMedGoogle Scholar
  31. 31.
    Guo Z, Yang X, Sun F et al (2009) A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 69(6):2305–2313PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Hagan CR, Lange CA (2014) Molecular determinants of context-dependent progesterone receptor action in breast cancer. BMC Med 12:32PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    He S, Zhang C, Shafi AA et al (2013) Potent activity of the Hsp90 inhibitor ganetespib in prostate cancer cells irrespective of androgen receptor status or variant receptor expression. Int J Oncol 42(1):35–43PubMedPubMedCentralGoogle Scholar
  34. 34.
    Higano CS, Crawford ED (2011) New and emerging agents for the treatment of castration-resistant prostate cancer. Urol Oncol Semin Orig Investig 29(6, Supplement):1–8CrossRefGoogle Scholar
  35. 35.
    Hirano D, Okada Y, Minei S et al (2004) Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol 45(5):586–592, discussion 592PubMedCrossRefGoogle Scholar
  36. 36.
    Hörnberg E, Ylitalo EB, Crnalic S et al (2011) Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS ONE 6(4):e19059PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Hu R, Denmeade SR, Luo J (2010) Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer. Expert Rev Endocrinol Metab 5(5):753–764PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Hu R, Dunn TA, Wei S et al (2009) Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69(1):16–22PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    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):1656–1667PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Hu R, Lu C, Mostaghel EA, et al (2012) Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res acceptedGoogle Scholar
  41. 41.
    Huang J, Yao JL, Zhang L et al (2005) Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. Am J Pathol 166(6):1807–1815PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Huggins C, Hodges CV (2002) Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 167(2 Pt 2):948–951, discussion 952PubMedCrossRefGoogle Scholar
  43. 43.
    Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRefGoogle Scholar
  44. 44.
    Joseph JD, Lu N, Jing Q, et al (2013) A clinically relevant androgen receptor mutation confers resistance to 2nd generation anti-androgens enzalutamide and ARN-509. Cancer DiscoveryGoogle Scholar
  45. 45.
    Knudsen KE, Scher HI (2009) Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 15(15):4792–4798PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Korpal M, Korn JM, Gao X et al (2013) An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 3(9):1030–1043PubMedCrossRefGoogle Scholar
  47. 47.
    Levine PM, Imberg K, Garabedian MJ et al (2012) Multivalent peptidomimetic conjugates: a versatile platform for modulating androgen receptor activity. J Am Chem Soc 134(16):6912–6915PubMedCrossRefGoogle Scholar
  48. 48.
    Li Y, Alsagabi M, Fan D et al (2011) Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res 71(6):2108–2117PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Li Y, Chan SC, Brand LJ et al (2013) Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73(2):483–489PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Li Y, Hwang TH, Oseth L, et al (2012) AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene In PressGoogle Scholar
  51. 51.
    Lim AC, Attard G (2013) Improved therapeutic targeting of the androgen receptor: rational drug design improves survival in castration-resistant prostate cancer. Curr Drug Targets 14(4):408–419PubMedCrossRefGoogle Scholar
  52. 52.
    Lin TH, Izumi K, Lee SO et al (2013) Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (enzalutamide) or Casodex (bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis 4:e764PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Liu C, Lou W, Zhu Y et al (2014) Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res 20(12):3198–3210PubMedCrossRefGoogle Scholar
  54. 54.
    Liu G, Cynthia S, Shihua S et al (2013) AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia 15(9):1009, New York, NYPubMedPubMedCentralGoogle Scholar
  55. 55.
    Liu LL, Xie N, Sun S, et al (2013) Mechanisms of the androgen receptor splicing in prostate cancer cells. OncogeneGoogle Scholar
  56. 56.
    Liu W, Laitinen S, Khan S et al (2009) Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 15(5):559–565PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Locke JA, Guns ES, Lubik AA et al (2008) Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68(15):6407–6415PubMedCrossRefGoogle Scholar
  58. 58.
    Merson S, Yang ZH, Brewer D et al (2014) Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. Br J Cancer 110(6):1655–1662PubMedCrossRefGoogle Scholar
  59. 59.
    Mohler JL, Gregory CW, Ford OH 3rd et al (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10(2):440–448PubMedCrossRefGoogle Scholar
  60. 60.
    Mostaghel EA, Marck BT, Plymate SR et al (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):5913–5925PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Myung JK, Banuelos CA, Fernandez JG et al (2013) An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest 123(7):2948–2960PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Nadal R, Schweizer M, Kryvenko ON et al (2014) Small cell carcinoma of the prostate. Nat Rev Urol 11(4):213–219PubMedCrossRefGoogle Scholar
  63. 63.
    Nadiminty N, Tummala R, Liu C et al (2013) NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther 12(8):1629–1637PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Nakka M, Agoulnik IU, Weigel NL (2013) Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells. Int J Biochem Cell Biol 45(4):763–772PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Nelson PS (2012) Molecular states underlying androgen receptor activation: a framework for therapeutics targeting androgen signaling in prostate cancer. J Clin Oncol 30(6):644–646PubMedCrossRefGoogle Scholar
  66. 66.
    Nyquist MD, Li Y, Hwang TH et al (2013) TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer. Proc Natl Acad Sci U S A 110(43):17492–17497PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Palmbos PL, Hussain M (2013) Non-castrate metastatic prostate cancer: have the treatment options changed? Semin Oncol 40(3):337–346PubMedCrossRefGoogle Scholar
  68. 68.
    Palmgren JS, Karavadia SS, Wakefield MR (2007) Unusual and underappreciated: small cell carcinoma of the prostate. Semin Oncol 34(1):22–29PubMedCrossRefGoogle Scholar
  69. 69.
    Plymate SR, Luo J (2013) The expression signature of androgen receptor splice variants and their distinctive transcriptional activities in castration-resistant prostate cancer. In Androgen-Responsive Genes in Prostate Cancer, 201–213. SpringerGoogle Scholar
  70. 70.
    Ryan CJ, Smith MR, de Bono JS et al (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368(2):138–148PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Sadar MD (2011) Small molecule inhibitors targeting the “Achilles’ heel” of androgen receptor activity. Cancer Res 71(4):1208–1213PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Sahu B, Laakso M, Pihlajamaa P et al (2013) FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res 73(5):1570–1580PubMedCrossRefGoogle Scholar
  73. 73.
    Sarker D, Reid AHM, Yap TA et al (2009) Targeting the PI3K/AKT Pathway for the treatment of prostate cancer. Clin Cancer Res 15(15):4799–4805PubMedCrossRefGoogle Scholar
  74. 74.
    Scher HI, Beer TM, Higano CS et al (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375(9724):1437–1446PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Scher HI, Buchanan G, Gerald W et al (2004) Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer. Endocr Relat Cancer 11(3):459–476PubMedCrossRefGoogle Scholar
  76. 76.
    Scher HI, Sawyers CL (2005) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23(32):8253–8261PubMedCrossRefGoogle Scholar
  77. 77.
    Scher HI, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367(13):1187–1197PubMedCrossRefGoogle Scholar
  78. 78.
    Schmidt LJ, Tindall DJ (2013) Androgen receptor: past, present and future. Curr Drug Targets 14(4):401–407PubMedCrossRefGoogle Scholar
  79. 79.
    Schweizer MT, Antonarakis ES (2012) Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. Ther Adv Urol 4(4):167–178PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Shafi AA, Yen AE, Weigel NL (2013) Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther 140(3):223–238PubMedCrossRefGoogle Scholar
  81. 81.
    Sharifi N, Gulley JL, Dahut WL (2005) Androgen deprivation therapy for prostate cancer. JAMA 294(2):238–244PubMedCrossRefGoogle Scholar
  82. 82.
    Steinkamp MP, O’Mahony OA, Brogley M et al (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 69(10):4434–4442PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Sun F, Chen H-g, Li W et al (2014) Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem 289(3):1529–1539PubMedCrossRefGoogle Scholar
  84. 84.
    Sun S, Sprenger CC, Vessella RL et al (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120(8):2715–2730PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Szmulewitz RZ, Chung E, Al-Ahmadie H et al (2012) Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. Prostate 72(2):157–164PubMedCrossRefGoogle Scholar
  86. 86.
    Taplin ME, Bubley GJ, Shuster TD et al (1995) Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332(21):1393–1398PubMedCrossRefGoogle Scholar
  87. 87.
    Taplin M-E, Montgomery RB, Logothetis C, et al (2012) Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): results of a randomized phase II study. In ASCO Meeting AbstractsGoogle Scholar
  88. 88.
    Titus MA, Schell MJ, Lih FB et al (2005) Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 11(13):4653–4657PubMedCrossRefGoogle Scholar
  89. 89.
    Tombal B, Borre M, Rathenborg P, et al (2014) Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet OncolGoogle Scholar
  90. 90.
    Tran C, Ouk S, Clegg NJ et al (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928):787–790PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Tzelepi V, Zhang J, Jing-Fang L et al (2012) Modeling a lethal prostate cancer variant with small-cell carcinoma features. Clin Cancer Res 18(3):666–677PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Visakorpi T, Hyytinen E, Koivisto P et al (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9(4):401–406PubMedCrossRefGoogle Scholar
  93. 93.
    Ware KE, Garcia-Blanco MA, Armstrong AJ, et al (2014) Significance of androgen receptor variants in castration resistant prostate cancer. Endocr Relat CancerGoogle Scholar
  94. 94.
    Watson PA, Chen YF, Balbas MD et al (2010) Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A 107(39):16759–16765PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Watson PA, Chen YF, Balbas MD, et al (2010) Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad SciGoogle Scholar
  96. 96.
    Yamashita S, Lai KP, Chuang KL et al (2012) ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia 14(1):74–83PubMedPubMedCentralGoogle Scholar
  97. 97.
    Yeh S, Miyamoto H, Shima H et al (1998) From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci U S A 95(10):5527–5532PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Yu Y, Liu L, Xie N et al (2013) Expression and function of the progesterone receptor in human prostate stroma provide novel insights to cell proliferation control. J Clin Endocrinol Metab 98(7):2887–2896PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Yu Z, Chen S, Sowalsky AG, et al (2014) Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res: clincanres. 1863.2013Google Scholar
  100. 100.
    YuanX, Cai C, Chen S, et al (2013) Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. OncogeneGoogle Scholar
  101. 101.
    Zhang X, Morrissey C, Sun S et al (2011) Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS ONE 6(11):e27970PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Zhao X-Y, Malloy PJ, Krishnan AV et al (2000) Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 6(6):703–706PubMedCrossRefGoogle Scholar
  103. 103.
    Zhu H, Garcia JA (2013) Targeting the adrenal gland in castration-resistant prostate cancer: a case for orteronel, a selective CYP-17 17,20-lyase inhibitor. Curr Oncol Rep 15(2):105–112PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mary Nakazawa
    • 1
  • Emmanuel S. Antonarakis
    • 2
  • Jun Luo
    • 1
    Email author
  1. 1.The James Buchanan Brady Urological Institute and Department of UrologyThe Johns Hopkins School of MedicineBaltimoreUSA
  2. 2.Department of OncologyThe Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA

Personalised recommendations