Androgen Receptor Regulation of Prostate Cancer Progression and Metastasis

  • R. S. Schrecengost
  • M. A. Augello
  • Karen E. Knudsen
Chapter
First Online:

Abstract

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and the second most lethal cancer in men amongst the United States. Localized tumors are effectively treated via radical prostatectomy and/or radiation therapy, however disseminated disease contributes greatly to patient morbidity. At present, therapeutic intervention for metastatic disease capitalizes on the addiction of these tumors to the androgen receptor (AR). The AR signaling axis regulates cell growth, proliferation, and migration of cancer cells, which makes understanding the contribution of AR toward these signaling pathways integral for PCa eradication. Several key signaling molecules are currently known to be controlled by AR and promote migration and invasion in castrate-resistant PCa (CRPC). This concept will be explored with regard to the interplay between AR and chemokine receptors, chromosomal fusions, oncogenes, and microRNAs. Additionally, current and preclinical AR-directed therapeutics used for treatment of metastatic PCa, which impinge on these pathways, and overall AR activity, will be discussed.

Keywords

Androgen Receptor Androgen Receptor Expression Abiraterone Acetate Androgen Receptor Signaling Ezrin Expression 
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.

Abbreviations

Abiraterone

Abiraterone acetate

ADT

Androgen deprivation therapy

AR

Androgen receptor

BC

Bicalutamide (Casodex)

CDKS

Cyclin-dependent kinases

CML

Chronic myelogenous leukemia

CRPC

Castration resistant prostate cancer

CTCs

Circulating tumor cells

DHT

5α-dihydrotestosterone

E-Box

Enhancer box

ETS

Erythroblast transformation specific transcription factor

FAK

Focal adhesion kinase

FISH

Florescence in-situ hybridization

Flutamide

Hydroxyflutamide

GnRH

Gonadotropin releasing hormone

HATs

Histone acetyltransferases

HSPs

Heat shock proteins

IHC

Immunohistochemistry

KLF5

Kruppel-like-factor 5

LBD

Ligand binding domain

MMPs

Matrix metalloproteinases

miRNA

MicroRNA

MYC

c-Myc

NCoR1

Nuclear Co-Repressor 1

PIN

Prostatic intraepithelial neoplasia

PcG

Polycomb-group

PCa

Prostate cancer

PSA

Prostate specific antigen

SDF-1

Stromal cell-derived factor 1

SFK

Macrophage inflammatory protein

SRC

Steroid receptor coactivator

TRAMP

Transgenic adenocarcinoma of the mouse prostate

TMPRSS2

Transmembrane protease serine 2

VCaP

Vertebral-Cancer of the Prostate

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Notes

Acknowledgements

We would like to thank all the members of the K. Knudsen lab, especially M. Schiewer, for insightful feedback and critical reading of this chapter.

References

  1. 1.
    Jemal A et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96PubMedGoogle Scholar
  2. 2.
    Klein EA et al (2009) Outcomes for intermediate risk prostate cancer: are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol 27(1):67–71PubMedGoogle Scholar
  3. 3.
    Klotz L (2006) Combined androgen blockade: an update. Urol Clin North Am 33(2):161–166, v–viPubMedGoogle Scholar
  4. 4.
    Knudsen KE, Scher HI (2009) Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 15(15):4792–4798PubMedGoogle Scholar
  5. 5.
    Loblaw DA et al (2007) 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 25(12):1596–1605PubMedGoogle Scholar
  6. 6.
    Yuan X, Balk SP (2009) Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol 27(1):36–41PubMedGoogle Scholar
  7. 7.
    Lawton CA et al (2001) Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85–31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49(4):937–946PubMedGoogle Scholar
  8. 8.
    Bolla M et al (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360(9327):103–106PubMedGoogle Scholar
  9. 9.
    Bubendorf L et al (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31(5):578–583PubMedGoogle Scholar
  10. 10.
    Cunha GR et al (2004) Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development. J Steroid Biochem Mol Biol 92(4):221–236PubMedGoogle Scholar
  11. 11.
    Penning TM et al (2008) Pre-receptor regulation of the androgen receptor. Mol Cell Endocrinol 281(1–2):1–8PubMedGoogle Scholar
  12. 12.
    Centenera MM et al (2008) The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol 22(11):2373–2382PubMedGoogle Scholar
  13. 13.
    Chmelar R et al (2007) Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer 120(4):719–733PubMedGoogle Scholar
  14. 14.
    Agoulnik IU, Weigel NL (2008) Androgen receptor coactivators and prostate cancer. Adv Exp Med Biol 617:245–255PubMedGoogle Scholar
  15. 15.
    Balk SP, Knudsen KE (2008) AR, the cell cycle, and prostate cancer. Nucl Recept Signal 6:e001PubMedGoogle Scholar
  16. 16.
    Beekman KW, Hussain M (2008) Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient. Urol Oncol 26(4):415–419PubMedGoogle Scholar
  17. 17.
    Ryan CJ et al (2006) Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression. Urology 68(4):834–839PubMedGoogle Scholar
  18. 18.
    Knudsen KE, Penning TM (2010) Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 21(5):315–324PubMedGoogle Scholar
  19. 19.
    Chen Y, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8(4):440–448PubMedGoogle Scholar
  20. 20.
    van Poppel H, Nilsson S (2008) Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology 71(6):1001–1006PubMedGoogle Scholar
  21. 21.
    Oefelein MG (1998) Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study consideration. J Urol 160(5):1685–1688PubMedGoogle Scholar
  22. 22.
    Linja MJ et al (2001) Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61(9):3550–3555PubMedGoogle Scholar
  23. 23.
    Latil A et al (2001) Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res 61(5):1919–1926PubMedGoogle Scholar
  24. 24.
    Ford OH 3rd et al (2003) Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol 170(5):1817–1821PubMedGoogle Scholar
  25. 25.
    Edwards J et al (2003) Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89(3):552–556PubMedGoogle Scholar
  26. 26.
    Sharma A et al (2010) The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 120(12):4478–4492Google Scholar
  27. 27.
    Donovan MJ et al (2010) Androgen receptor expression is associated with prostate cancer-specific survival in castrate patients with metastatic disease. BJU Int 105(4):462–467PubMedGoogle Scholar
  28. 28.
    Taplin ME (2007) Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol 4(4):236–244PubMedGoogle Scholar
  29. 29.
    Brooke GN, Bevan CL (2009) The role of androgen receptor mutations in prostate cancer progression. Curr Genomics 10(1):18–25PubMedGoogle Scholar
  30. 30.
    Middleman MN, Lush RM, Figg WD (1996) The mutated androgen receptor and its implications for the treatment of metastatic carcinoma of the prostate. Pharmacotherapy 16(3):376–381PubMedGoogle Scholar
  31. 31.
    Dehm SM 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):5469–5477PubMedGoogle Scholar
  32. 32.
    Hu R et al (2009) Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 69(1):16–22PubMedGoogle Scholar
  33. 33.
    Guo Z 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):2305–2313PubMedGoogle Scholar
  34. 34.
    Jenster G et al (1995) Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 270(13):7341–7346PubMedGoogle Scholar
  35. 35.
    Xu J, Wu RC, O’Malley BW (2009) Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer 9(9):615–630PubMedGoogle Scholar
  36. 36.
    Gregory CW et al (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61(11):4315–4319PubMedGoogle Scholar
  37. 37.
    Agoulnik IU et al (2005) Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res 65(17):7959–7967PubMedGoogle Scholar
  38. 38.
    Agoulnik IU, Weigel NL (2009) Coactivator selective regulation of androgen receptor activity. Steroids 74(8):669–674PubMedGoogle Scholar
  39. 39.
    Comuzzi B et al (2003) 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 162(1):233–241PubMedGoogle Scholar
  40. 40.
    Shang Y, Myers M, Brown M (2002) Formation of the androgen receptor transcription complex. Mol Cell 9(3):601–610PubMedGoogle Scholar
  41. 41.
    Burd CJ, Morey LM, Knudsen KE (2006) Androgen receptor corepressors and prostate cancer. Endocr Relat Cancer 13(4):979–994PubMedGoogle Scholar
  42. 42.
    Knudsen KE (2006) The cyclin D1b splice variant: an old oncogene learns new tricks. Cell Div 1:15PubMedGoogle Scholar
  43. 43.
    Comstock CE et al (2009) Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer. Clin Cancer Res 15(17):5338–5349PubMedGoogle Scholar
  44. 44.
    Montgomery RB et al (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68(11):4447–4454PubMedGoogle Scholar
  45. 45.
    Wang Q et al (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138(2):245–256PubMedGoogle Scholar
  46. 46.
    Wang Q et al (2007) A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 27(3):380–392PubMedGoogle Scholar
  47. 47.
    Sobel RE, Sadar MD (2005) Cell lines used in prostate cancer research: a compendium of old and new lines–part 1. J Urol 173(2):342–359PubMedGoogle Scholar
  48. 48.
    Furusato B et al (2010) CXCR4 and cancer. Pathol Int 60(7):497–505PubMedGoogle Scholar
  49. 49.
    Sun X et al (2010) CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 29(4):709–722PubMedGoogle Scholar
  50. 50.
    Vindrieux D, Escobar P, Lazennec G (2009) Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer 16(3):663–673PubMedGoogle Scholar
  51. 51.
    Sun YX et al (2003) Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem 89(3):462–473PubMedGoogle Scholar
  52. 52.
    Fernandis AZ et al (2004) Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene 23(1):157–167PubMedGoogle Scholar
  53. 53.
    Prasad A et al (2004) Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells. J Biol Chem 279(10):9115–9124PubMedGoogle Scholar
  54. 54.
    Kukreja P et al (2005) Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res 65(21):9891–9898PubMedGoogle Scholar
  55. 55.
    Wang JF, Park IW, Groopman JE (2000) Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood 95(8):2505–2513PubMedGoogle Scholar
  56. 56.
    Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18(5):516–523PubMedGoogle Scholar
  57. 57.
    McGrath KE et al (1999) Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. Dev Biol 213(2):442–456PubMedGoogle Scholar
  58. 58.
    Sun YX et al (2005) Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res 20(2):318–329PubMedGoogle Scholar
  59. 59.
    Frigo DE et al (2009) Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro. Mol Endocrinol 23(9):1385–1396PubMedGoogle Scholar
  60. 60.
    Mochizuki H et al (2004) Interaction of ligand-receptor system between stromal-cell-derived factor-1 and CXC chemokine receptor 4 in human prostate cancer: a possible predictor of metastasis. Biochem Biophys Res Commun 320(3):656–663PubMedGoogle Scholar
  61. 61.
    Kazmin D et al (2006) Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators. Mol Endocrinol 20(6):1201–1217PubMedGoogle Scholar
  62. 62.
    Jamieson WL et al (2008) CX3CR1 is expressed by prostate epithelial cells and androgens regulate the levels of CX3CL1/fractalkine in the bone marrow: potential role in prostate cancer bone tropism. Cancer Res 68(6):1715–1722PubMedGoogle Scholar
  63. 63.
    Tomlins SA et al (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–648PubMedGoogle Scholar
  64. 64.
    Mehra R et al (2008) Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res 68(10):3584–3590PubMedGoogle Scholar
  65. 65.
    Iljin K et al (2006) TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res 66(21):10242–10246PubMedGoogle Scholar
  66. 66.
    Mani RS et al (2009) Induced chromosomal proximity and gene fusions in prostate cancer. Science 326(5957):1230PubMedGoogle Scholar
  67. 67.
    Lin C et al (2009) Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139(6):1069–1083PubMedGoogle Scholar
  68. 68.
    Mertz KD et al (2007) Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9(3):200–206PubMedGoogle Scholar
  69. 69.
    Bastus CN et al (2010) Androgen-induced TMPRSS2:ERG fusion in non-malignant prostate epithelial cells. Cancer Res 70(23):9544–9548Google Scholar
  70. 70.
    Hendriksen PJ et al (2006) Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res 66(10):5012–5020PubMedGoogle Scholar
  71. 71.
    Tomlins SA et al (2008) Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 10(2):177–188PubMedGoogle Scholar
  72. 72.
    Klezovitch O et al (2008) A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci USA 105(6):2105–2110PubMedGoogle Scholar
  73. 73.
    Cai J et al (2010) Androgens induce functional CXCR4 through ERG factor expression in TMPRSS2-ERG fusion-positive prostate cancer cells. Transl Oncol 3(3):195–203PubMedGoogle Scholar
  74. 74.
    Zong Y et al (2009) ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc Natl Acad Sci USA 106(30):12465–12470PubMedGoogle Scholar
  75. 75.
    Wang J et al (2006) Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res 66(17):8347–8351PubMedGoogle Scholar
  76. 76.
    Wang J et al (2008) Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. Cancer Res 68(20):8516–8524PubMedGoogle Scholar
  77. 77.
    Mehra R et al (2007) Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol 20(5):538–544PubMedGoogle Scholar
  78. 78.
    Mosquera JM et al (2008) Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 14(11): 3380–3385PubMedGoogle Scholar
  79. 79.
    Selbach M et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455(7209):58–63PubMedGoogle Scholar
  80. 80.
    Dastugue N et al (2002) Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 100(2):618–626PubMedGoogle Scholar
  81. 81.
    Sorensen PH et al (1994) A second Ewing’s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 6(2):146–151PubMedGoogle Scholar
  82. 82.
    Demichelis F et al (2007) TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26(31):4596–4599PubMedGoogle Scholar
  83. 83.
    Laxman B et al (2008) A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res 68(3):645–649PubMedGoogle Scholar
  84. 84.
    Laxman B et al (2006) Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia 8(10):885–888PubMedGoogle Scholar
  85. 85.
    Rostad K et al (2009) TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis. APMIS 117(8):575–582PubMedGoogle Scholar
  86. 86.
    Coppola V, De Maria R, Bonci D (2010) MicroRNAs and prostate cancer. Endocr Relat Cancer 17(1):F1–F17PubMedGoogle Scholar
  87. 87.
    Garzon R, Marcucci G, Croce CM (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9(10):775–789PubMedGoogle Scholar
  88. 88.
    Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838PubMedGoogle Scholar
  89. 89.
    Calin GA et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101(9):2999–3004PubMedGoogle Scholar
  90. 90.
    Volinia S et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103(7):2257–2261PubMedGoogle Scholar
  91. 91.
    Narayanan R et al (2010) MicroRNAs are mediators of androgen action in prostate and muscle. PLoS One 5(10):e13637PubMedGoogle Scholar
  92. 92.
    Ambs S et al (2008) Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 68(15):6162–6170PubMedGoogle Scholar
  93. 93.
    Ribas J et al (2009) miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 69(18):7165–7169PubMedGoogle Scholar
  94. 94.
    Shi XB et al (2007) An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci USA 104(50):19983–19988PubMedGoogle Scholar
  95. 95.
    Varambally S et al (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322(5908):1695–1699PubMedGoogle Scholar
  96. 96.
    Wang HJ et al (2010) MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer 46(12):2295–2303PubMedGoogle Scholar
  97. 97.
    Cao P et al (2010) MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer 9:108PubMedGoogle Scholar
  98. 98.
    Schulz WA, Hatina J (2006) Epigenetics of prostate cancer: beyond DNA methylation. J Cell Mol Med 10(1):100–125PubMedGoogle Scholar
  99. 99.
    Lawrie CH (2007) MicroRNA expression in lymphoma. Expert Opin Biol Ther 7(9):1363–1374PubMedGoogle Scholar
  100. 100.
    Navarro A et al (2008) MicroRNA expression profiling in classic Hodgkin lymphoma. Blood 111(5):2825–2832PubMedGoogle Scholar
  101. 101.
    Wang G et al (2008) Transcription factor and microRNA regulation in androgen-dependent and -independent prostate cancer cells. BMC Genomics 9(Suppl 2):S22PubMedGoogle Scholar
  102. 102.
    Li T et al (2009) MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun 383(3):280–285PubMedGoogle Scholar
  103. 103.
    Lin SL et al (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14(3):417–424PubMedGoogle Scholar
  104. 104.
    Wang L et al (2009) Gene networks and microRNAs implicated in aggressive prostate cancer. Cancer Res 69(24):9490–9497PubMedGoogle Scholar
  105. 105.
    Gallucci M et al (2006) Cytogenetic profiles as additional markers to pathological features in clinically localized prostate carcinoma. Cancer Lett 237(1):76–82PubMedGoogle Scholar
  106. 106.
    Gallucci M et al (2009) Genetic profile identification in clinically localized prostate carcinoma. Urol Oncol 27(5):502–508PubMedGoogle Scholar
  107. 107.
    Leversha MA et al (2009) Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res 15(6):2091–2097PubMedGoogle Scholar
  108. 108.
    Jenkins RB et al (1997) Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res 57(3):524–531PubMedGoogle Scholar
  109. 109.
    Sato K et al (1999) Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J Natl Cancer Inst 91(18):1574–1580PubMedGoogle Scholar
  110. 110.
    Iwata T et al (2010) MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PLoS One 5(2):e9427PubMedGoogle Scholar
  111. 111.
    Ellwood-Yen K et al (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4(3):223–238PubMedGoogle Scholar
  112. 112.
    Watson PA et al (2005) Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line. Cancer Res 65(24):11565–11571PubMedGoogle Scholar
  113. 113.
    Visakorpi T et al (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9(4):401–406PubMedGoogle Scholar
  114. 114.
    Chuan YC et al (2010) Ezrin mediates c-Myc actions in prostate cancer cell invasion. Oncogene 29(10):1531–1542PubMedGoogle Scholar
  115. 115.
    Silva IS et al (2001) Androgen-induced cell growth and c-myc expression in human non-transformed epithelial prostatic cells in primary culture. Endocr Res 27(1–2):153–169PubMedGoogle Scholar
  116. 116.
    Sun C et al (2008) TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene 27(40):5348–5353PubMedGoogle Scholar
  117. 117.
    Grad JM et al (1999) Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Mol Endocrinol 13(11):1896–1911PubMedGoogle Scholar
  118. 118.
    Khanna C et al (2004) The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10(2):182–186PubMedGoogle Scholar
  119. 119.
    Yu Y et al (2004) Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10(2):175–181PubMedGoogle Scholar
  120. 120.
    Chuan YC et al (2006) Androgen induction of prostate cancer cell invasion is mediated by ezrin. J Biol Chem 281(40):29938–29948PubMedGoogle Scholar
  121. 121.
    Nupponen NN et al (1998) Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am J Pathol 153(1):141–148PubMedGoogle Scholar
  122. 122.
    de Bono JS et al (2008) Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res 14(20):6663–6673PubMedGoogle Scholar
  123. 123.
    Kaltz-Wittmer C et al (2000) FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy. Lab Invest 80(9):1455–1464PubMedGoogle Scholar
  124. 124.
    Gurel B et al (2008) Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol 21(9):1156–1167PubMedGoogle Scholar
  125. 125.
    Hawksworth D et al (2010) Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Prostate Cancer Prostatic Dis 13(4):311–315PubMedGoogle Scholar
  126. 126.
    Wolfer A et al (2010) MYC regulation of a “poor-prognosis” metastatic cancer cell state. Proc Natl Acad Sci USA 107(8):3698–3703PubMedGoogle Scholar
  127. 127.
    Martin GS (1970) Rous sarcoma virus: a function required for the maintenance of the transformed state. Nature 227(5262):1021–1023PubMedGoogle Scholar
  128. 128.
    Saad F, Lipton A (2010) SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev 36(2):177–184PubMedGoogle Scholar
  129. 129.
    Guo Z et al (2006) Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell 10(4):309–319PubMedGoogle Scholar
  130. 130.
    Kraus S et al (2006) Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer Res 66(22):11047–11054PubMedGoogle Scholar
  131. 131.
    Asim M et al (2008) Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells. Oncogene 27(25):3596–3604PubMedGoogle Scholar
  132. 132.
    Gingrich JR et al (1997) Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res 57(21):4687–4691PubMedGoogle Scholar
  133. 133.
    Tatarov O et al (2009) SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res 15(10):3540–3549PubMedGoogle Scholar
  134. 134.
    Araujo J, Logothetis C (2010) Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors. Cancer Treat Rev 36(6):492–500PubMedGoogle Scholar
  135. 135.
    Park SI et al (2008) Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res 68(9):3323–3333PubMedGoogle Scholar
  136. 136.
    Labrie F et al (2005) Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev 26(3):361–379PubMedGoogle Scholar
  137. 137.
    Shepard DR, Raghavan D (2010) Innovations in the systemic therapy of prostate cancer. Nat Rev Clin Oncol 7(1):13–21PubMedGoogle Scholar
  138. 138.
    Haidar S et al (2003) Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84(5):555–562PubMedGoogle Scholar
  139. 139.
    Attard G 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):4563–4571PubMedGoogle Scholar
  140. 140.
    Reid AH et al (2010) Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 28(9):1489–1495PubMedGoogle Scholar
  141. 141.
    Tran C et al (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928):787–790PubMedGoogle Scholar
  142. 142.
    Culig Z et al (1999) Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer 81(2):242–251PubMedGoogle Scholar
  143. 143.
    Scher HI et al (2010) Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375(9724):1437–1446PubMedGoogle Scholar
  144. 144.
    Handratta VD et al (2005) Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem 48(8):2972–2984PubMedGoogle Scholar
  145. 145.
    Vasaitis T et al (2008) Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther 7(8):2348–2357PubMedGoogle Scholar
  146. 146.
    Andersen RJ 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):535–546PubMedGoogle Scholar
  147. 147.
    Shen R et al (2000) Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Endocrinology 141(5):1699–1704PubMedGoogle Scholar
  148. 148.
    Xu K et al (2009) Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell 15(4):270–282PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • R. S. Schrecengost
    • 1
    • 2
  • M. A. Augello
    • 1
    • 2
  • Karen E. Knudsen
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Cancer BiologyThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Kimmel Cancer Center, Thomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Department of UrologyThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Radiation OncologyThomas Jefferson UniversityPhiladelphiaUSA

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