Androgen receptor signaling in prostate cancer development and progression

Peter Lonergan, Donald Tindall

Research output: Contribution to journalArticle

238 Scopus citations

Abstract

The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined. Lonergan Peter 1 Department of Urology, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota Tindall Donald 2 Department of Urology, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin 2010;60:277-300. Klein EA, Ciezki J, Kupelian PA, Mahadevan A. Outcomes for intermediate risk prostate cancer: are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol 2009;27:67-71. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007;25:1596-605. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res 2006;12:1665-71. Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, et al. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol 1994;144:735-46. Chodak GW, Kranc DM, Puy LA, Takeda H, Johnson K, Chang C. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol 1992;147:798-803. Sadi MV, Walsh PC, Barrack ER. Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. Cancer 1991;67:3057-64. Henshall SM, Quinn DI, Lee CS, Head DR, Golovsky D, Brenner PC, et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res 2001;61:423-7. Ricciardelli C, Choong CS, Buchanan G, Vivekanandan S, Neufing P, Stahl J, et al. Androgen receptor levels in prostate cancer epithelial and peritumoral stromal cells identify non-organ confined disease. Prostate 2005;63:19-28. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33-9. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer 2001;1:34-45. Scher HI, Buchanan G, Gerald W, Butler LM, Tilley WD. Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer. Endocr Relat Cancer 2004;11:459-76. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23:8253-61. Ryan CJ, Smith A, Lal P, Satagopan J, Reuter V, Scardino P, et al. Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression. Urology 2006;68:834-9. Buchanan G, Irvine RA, Coetzee GA, Tilley WD. Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev 2001;20:207-23. Steinkamp MP, O′Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 2009;69:4434-42. 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. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 2007;28:778-808. Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 2008;15:841-9. Bergerat JP, Ceraline J. Pleiotropic functional properties of androgen receptor mutants in prostate cancer. Hum Mutat 2009;30:145-57. Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A. Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal 2008;6:e008. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol 2002;20:3001-15. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004;25:276-308. Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 1991;5:1396-404. Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem 1991;266:510-8. Jenster G, van der Korput HA, Trapman J, Brinkmann AO. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 1995;270:7341-6. Callewaert L, Van Tilborgh N, Claessens F. Interplay between two hormone-independent activation domains in the androgen receptor. Cancer Res 2006;66:543-53. Chamberlain NL, Whitacre DC, Miesfeld RL. Delineation of two distinct type 1 activation functions in the androgen receptor amino-terminal domain. J Biol Chem 1996;271:26772-8. Dehm SM, Regan KM, Schmidt LJ, Tindall DJ. Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells. Cancer Res 2007;67:10067-77. Umesono K, Evans RM. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 1989;57:1139-46. Ozanne DM, Brady ME, Cook S, Gaughan L, Neal DE, Robson CN. Androgen receptor nuclear translocation is facilitated by the f-actin cross-linking protein filamin. Mol Endocrinol 2000;14:1618-26. Bedolla RG, Wang Y, Asuncion A, Chamie K, Siddiqui S, Mudryj MM, et al. Nuclear versus cytoplasmic localization of filamin A in prostate cancer: immunohistochemical correlation with metastases. Clin Cancer Res 2009;15:788-96. Kaku N, Matsuda K, Tsujimura A, Kawata M. Characterization of nuclear import of the domain-specific androgen receptor in association with the importin alpha/beta and Ran-guanosine 5′-triphosphate systems. Endocrinology 2008;149:3960-9. Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997;387:733-6. Duff J, Davies P, Watt K, McEwan IJ. Structural dynamics of the human androgen receptor: implications for prostate cancer and neurodegenerative disease. Biochem Soc Trans 2006;34:1098-102. Buchanan G, Greenberg NM, Scher HI, Harris JM, Marshall VR, Tilley WD. Collocation of androgen receptor gene mutations in prostate cancer. Clin Cancer Res 2001;7:1273-81. 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. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptorgene in metastatic androgen-independent prostate cancer.

Original languageEnglish (US)
Article number20
JournalJournal of Carcinogenesis
Volume10
DOIs
StatePublished - Dec 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Health, Toxicology and Mutagenesis

Fingerprint Dive into the research topics of 'Androgen receptor signaling in prostate cancer development and progression'. Together they form a unique fingerprint.

  • Cite this