European Journal of Cancer
Volume 41, Issue 6 , Pages 858-887 , April 2005

Molecular markers of prostate cancer outcome

  • David I. Quinn

      Affiliations

    • Division of Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastalke Avenue, Suite 3453, Los Angeles, CA 90033, USA
    • Division of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC 20007, USA
    • Corresponding Author InformationCorresponding author. Address: Division of Oncology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastalke Avenue, Suite 3453, Los Angeles, CA 90033, USA. Tel.: +1 323 865 3956; fax: +1 323 865 0061
  • ,
  • Susan M. Henshall

      Affiliations

    • Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, NSW 2010, Australia
    • Division of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC 20007, USA
  • ,
  • Robert L. Sutherland

      Affiliations

    • Division of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC 20007, USA

Received 20 September 2004 ,Accepted 2 December 2004.

References 

  1. Kattan MW, Eastham JA, Stapleton AM, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998;90:766–771
  2. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol. 1999;17:1499–1507
  3. Quinn DI, Henshall SM, Haynes A-M, et al. Prognostic significance of pathologic features in localized prostate cancer treated with radical prostatectomy: implications for staging systems and predictive models. J Clin Oncol. 2001;19:3692–3705
  4. Quinn DI, Henshall SM, Brenner PC, et al. Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy. Cancer. 2003;97:1884–1893
  5. Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. J Clin Oncol. 2003;21:4568–4571
  6. Graefen M, Karakiewicz PI, Cagiannos I, et al. Validation study of the accuracy of a postoperative nomogram for recurrence after radical prostatectomy for localized prostate cancer. J Clin Oncol. 2002;20:951–956
  7. Graefen M, Karakiewicz PI, Cagiannos I, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2002;20:3206–3212
  8. Bostwick DG, Grignon DJ, Hammond ME, et al. Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124:995–1000
  9. Henshall SM, Afar DE, Rasiah KK, et al. Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer. Oncogene. 2003;22:6005–6012
  10. Henshall SM, Afar DE, Hiller J, et al. Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse. Cancer Res. 2003;63:4196–4203
  11. Horvath L, Henshall S. The application of tissue microarrays to cancer research. Pathology. 2001;33:125–129
  12. Welsh JB, Sapinoso LM, Kern SG, et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci USA. 2003;100:3410–3415
  13. Cher ML, Chew K, Rosenau W, et al. Cellular proliferation in prostatic adenocarcinoma as assessed by bromodeoxyuridine uptake and Ki-67 and PCNA expression. Prostate. 1995;26:87–93
  14. Keshgegian AA, Johnston E, Cnaan A. Bcl-2 oncoprotein positivity and high MIB-1 (Ki-67) proliferative rate are independent predictive markers for recurrence in prostate carcinoma. Am J Clin Pathol. 1998;110:443–449
  15. Harper ME, Glynne-Jones E, Goddard L, et al. Relationship of proliferating cell nuclear antigen (PCNA) in prostatic carcinomas to various clinical parameters. Prostate. 1992;20:243–253
  16. Nemoto R, Kawamura H, Miyakawa I, et al. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA)/cyclin in human prostate adenocarcinoma. J Urol. 1993;149:165–169
  17. Bubendorf L, Sauter G, Moch H, et al. Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol. 1996;178:437–441
  18. Cher ML, Stephenson RA, James BC, et al. Cellular proliferative fraction of metastatic lymph nodes predicts survival in stage D1 (TxN+M0) prostate cancer. J Urol. 1996;155:1674–1677
  19. Cheng L, Pisansky TM, Sebo TJ, et al. Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression. Clin Cancer Res. 1999;5:2820–2823
  20. Khoo VS, Pollack A, Cowen D, et al. Relationship of Ki-67 labeling index to DNA-ploidy, S-phase fraction, and outcome in prostate cancer treated with radiotherapy. Prostate. 1999;41:166–172
  21. Bubendorf L, Tapia C, Gasser TC, et al. Ki67 labeling index in core needle biopsies independently predicts tumor-specific survival in prostate cancer. Hum Pathol. 1998;29:949–954
  22. Oomens EH, van Steenbrugge GJ, van der Kwast TH, et al. Application of the monoclonal antibody Ki-67 on prostate biopsies to assess the fraction of human prostatic carcinoma. J Urol. 1991;145:81–85
  23. Grossfeld GD, Olumi AF, Connolly JA, et al. Locally recurrent prostate tumors following either radiation therapy or radical prostatectomy have changes in Ki-67 labeling index, p53 and bcl-2 immunoreactivity. J Urol. 1998;159:1437–1443
  24. Wheeler TM, Rogers E, Aihara M, et al. Apoptotic index as a biomarker in prostatic intraepithelial neoplasia (PIN) and prostate cancer. J Cell Biochem Suppl. 1994;19:202–207
  25. Aihara M, Scardino PT, Truong LD, et al. The frequency of apoptosis correlates with the prognosis of Gleason Grade 3 adenocarcinoma of the prostate. Cancer. 1995;75:522–529
  26. Stapleton AM, Zbell P, Kattan MW, et al. Assessment of the biologic markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery. Cancer. 1998;82:168–175
  27. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–330
  28. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–1163
  29. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–1677
  30. Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994;78:67–74
  31. Hall M, Bates S, Peters G. Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. Oncogene. 1995;11:1581–1588
  32. Macleod KF, Sherry N, Hannon G, et al. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995;9:935–944
  33. LaBaer J, Garrett MD, Stevenson LF, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997;11:847–862
  34. Sutherland RL, Musgrove EA. Cyclin E and prognosis in patients with breast cancer. N Engl J Med. 2002;347:1546–1547
  35. Ruas M, Peters G. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta. 1998;1378:F115–F177
  36. Liggett WH, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol. 1998;16:1197–1206
  37. Prall OW, Rogan EM, Musgrove EA, et al. c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol. 1998;18:4499–4508
  38. Amati B, Land H. Myc–Max–Mad: a transcription factor network controlling cell cycle progression, differentiation and death. Curr Opin Genet Dev. 1994;4:102–108
  39. Grad JM, Dai JL, Wu S, et al. 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. 1999;13:1896–1911
  40. Kokontis J, Takakura K, Hay N, et al. Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res. 1994;54:1566–1573
  41. Bookstein R, Rio P, Madreperla SA, et al. Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma. Proc Natl Acad Sci USA. 1990;87:7762–7766
  42. Geradts J, Hu SX, Lincoln CE, et al. Aberrant RB gene expression in routinely processed, archival tumor tissues determined by three different anti-RB antibodies. Int J Cancer. 1994;58:161–167
  43. Geradts J, Wilson PA. High frequency of aberrant p16(INK4A) expression in human breast cancer. Am J Pathol. 1996;149:15–20
  44. Susini T, Baldi F, Howard C, et al. Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer. J Clin Oncol. 1998;16:1085–1093
  45. Caputi M, Groeger AM, Esposito V, et al. Loss of pRb2/p130 expression is associated with unfavorable clinical outcome in lung cancer. Clin Cancer Res. 2002;8:3850–3856
  46. Cote RJ, Dunn MD, Chatterjee SJ, et al. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 1998;58:1090–1094
  47. Ittmann MM, Wieczorek R. Alterations of the retinoblastoma gene in clinically localized, stage B prostate adenocarcinomas. Hum Pathol. 1996;27:28–34
  48. Brooks JD, Bova GS, Isaacs WB. Allelic loss of the retinoblastoma gene in primary human prostatic adenocarcinomas. Prostate. 1995;26:35–39
  49. Phillips SM, Barton CM, et al. Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis. Br J Cancer. 1994;70:1252–1257
  50. Cooney KA, Wetzel JC, Merajver SD, et al. Distinct regions of allelic loss on 13q in prostate cancer. Cancer Res. 1996;56:1142–1145
  51. Melamed J, Einhorn JM, Ittman MM. Allelic loss on chromosome 13q in human prostate carcinoma. Clin Cancer Res. 1997;3:1867–1872
  52. Vesalainen S, Lipponen P. Expression of retinoblastoma gene (Rb) protein in T1-2M0 prostatic adenocarcinoma. J Cancer Res Clin Oncol. 1995;121:429–433
  53. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995;147:545–560
  54. Henshall SM, Quinn DI, Lee CS, et al. Overexpression of the cell cycle inhibitor p16INK4A in high-grade prostatic intraepithelial neoplasia predicts early relapse in prostate cancer patients. Clin Cancer Res. 2001;7:544–550
  55. Xiong Y, Menninger J, Beach D, et al. Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics. 1992;13:575–584
  56. Gumbiner LM, Gumerlock PH, Mack PC, et al. Overexpression of cyclin D1 is rare in human prostate carcinoma. Prostate. 1999;38:40–45
  57. Aaltomaa S, Eskelinen M, Lipponen P. Expression of cyclin A and D proteins in prostate cancer and their relation to clinopathological variables and patient survival. Prostate. 1999;38:175–182
  58. Kallakury BV, Sheehan CE, Ambros RA, et al. The prognostic significance of p34cdc2 and cyclin D1 protein expression in prostate adenocarcinoma. Cancer. 1997;80:753–763
  59. Porter PL, Malone KE, Heagerty PJ, et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med. 1997;3:222–225
  60. Iida H, Towatari M, Tanimoto M, et al. Overexpression of cyclin E in acute myelogenous leukemia. Blood. 1997;90:3707–3713
  61. Mashal RD, Lester S, Corless C, et al. Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res. 1996;56:4159–4163
  62. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–707
  63. Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all human cancers. Cancer Res. 1995;55:4525–4530
  64. Komiya A, Suzuki H, Aida S, et al. Mutational analysis of CDKN2 (CDK4I/MTS1) gene in tissues and cell lines of human prostate cancer. Jpn J Cancer Res. 1995;86:622–625
  65. Jarrard DF, Bova GS, Ewing CM, et al. Deletional, mutational, and methylation analyses of CDKN2 (p16/MTS1) in primary and metastatic prostate cancer. Genes, Chromosomes Cancer. 1997;19:90–96
  66. Cairns P, Polascik TJ, Eby Y, et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nature Genet. 1995;11:210–212
  67. Tamimi Y, Bringuier PP, Smit F, et al. p16 mutations/deletions are not frequent events in prostate cancer. Br J Cancer. 1996;74:120–122
  68. Gaddipati JP, McLeod DG, Sesterhenn IA, et al. Mutations of the p16 gene product are rare in prostate cancer. Prostate. 1997;30:188–194
  69. Chen W, Weghorst CM, Sabourin CLK, et al. Absence of p 16/MTS 1 gene mutations in human prostate cancer. Carcinogenesis. 1996;17:2603–2607
  70. Park DJ, Wilczynski SP, Pham EY, et al. Molecular analysis of the INK4 family of genes in prostate carcinomas. J Urol. 1997;157:1995–1999
  71. Lee CT, Capodieci P, Osman I, et al. Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer. Clin Cancer Res. 1999;5:977–983
  72. Halvorsen OJ, Hostmark J, Haukaas S, et al. Prognostic significance of p16 and CDK4 proteins in localized prostate carcinoma. Cancer. 2000;88:416–424
  73. Li Y, Nichols MA, Shay JW, et al. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994;54:6078–6082
  74. Jarrard DF, Sarkar S, Shi Y, et al. p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells. Cancer Res. 1999;59:2957–2964
  75. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999;50:401–423
  76. Gao X, Chen YQ, Wu N, et al. Somatic mutations of the WAF1/CIP1 gene in primary prostate cancer. Oncogene. 1995;11:1395–1398
  77. Rowan S, Ludwig RL, Haupt Y, et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 1996;15:827–838
  78. Wang J, Walsh K. Resistance to apoptosis conferred by Cdk inhibitors during myocyte differentiation. Science. 1996;273:359–361
  79. Osman I, Drobnjak M, Fazzari M, et al. Inactivation of the p53 pathway in prostate cancer: impact on tumor progression. Clin Cancer Res. 1999;5:2082–2088
  80. Russell A, Hendley J, Germain D. Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins. Oncogene. 1999;18:6454–6459
  81. Lu S, Liu M, Epner DE, et al. Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter. Mol Endocrinol. 1999;13:376–384
  82. Rigaud J, Tiguert R, Decobert M, et al. Expression of p21 cell cycle protein is an independent predictor of response to salvage radiotherapy after radical prostatectomy. Prostate. 2004;58:269–276
  83. Fizazi K, Martinez LA, Sikes CR, et al. The association of p21((WAF-1/CIP1)) with progression to androgen-independent prostate cancer. Clin Cancer Res. 2002;8:775–781
  84. Ponce-Castaneda MV, Lee MH, Latres E, et al. p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. Cancer Res. 1995;55:1211–1214
  85. Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27 (Kip1)-deficient mice. Cell. 1996;85:733–744
  86. Cordon-Cardo C, Koff A, Drobnjak M, et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst. 1998;90:1284–1291
  87. Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature Med. 1997;3:227–230
  88. Lloyd RV, Jin L, Qian X, et al. Aberrant p27kip1 expression in endocrine and other tumors. Am J Pathol. 1997;150:401–407
  89. Tan P, Cady B, Wanner M, et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res. 1997;57:1259–1263
  90. Fredersdorf S, Burns J, Milne AM, et al. High level expression of p27 (kip1) and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27 (kip1) and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA. 1997;94:6380–6385
  91. Esposito V, Baldi A, De Luca A, et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 1997;57:3381–3385
  92. Loda M, Cukor B, Tam SW, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med. 1997;3:231–234
  93. Singh SP, Lipman J, Goldman H, et al. Loss or altered subcellular localization of p27 in Barrett’s associated adenocarcinoma. Cancer Res. 1998;58:1730–1735
  94. Kawamata N, Morosetti R, Miller CW, et al. Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. Cancer Res. 1995;55:2266–2269
  95. Spirin KS, Simpson JF, Takeuchi S, et al. p27/Kip1 mutation found in breast cancer. Cancer Res. 1996;56:2400–2404
  96. Kibel AS, Freije D, Isaacs WB, et al. Deletion mapping at 12p12-13 in metastatic prostate cancer. Genes Chromosomes Cancer. 1999;25:270–276
  97. Pagano M, Tam SW, Theodoras AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995;269:682–685
  98. Millard SS, Yan JS, Nguyen H, et al. Enhanced ribosomal association of p27(Kip1) mRNA is a mechanism contributing to accumulation during growth arrest. J Biol Chem. 1997;272:7093–7098
  99. Vlach J, Hennecke S, Amati B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J. 1997;16:5334–5344
  100. Jin L, Qian X, Kulig E, et al. Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27Kip1 expression in nontumorous and neoplastic human pituitaries. Am J Pathol. 1997;151:509–519
  101. Vrhovac R, Delmer A, Tang R, et al. Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia. Blood. 1998;91:4694–4700
  102. Vlach J, Hennecke S, Alevizopoulos K, et al. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 1996;15:6595–6604
  103. Perez-Roger I, Solomon DL, Sewing A, et al. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27 (Kip1) binding to newly formed complexes. Oncogene. 1997;14:2373–2381
  104. Muller D, Bouchard C, Rudolph B, et al. Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes. Oncogene. 1997;15:2561–2576
  105. Sheaff RJ, Groudine M, Gordon M, et al. Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. 1997;11:1464–1478
  106. Kokontis JM, Hay N, Liao S. Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. Mol Endocrinol. 1998;12:941–953
  107. Myers RB, Oelschlager DK, Coan PN, et al. Changes in cyclin dependent kinase inhibitors p21 and p27 during the castration induced regression of the CWR22 model of prostatic adenocarcinoma. J Urol. 1999;161:945–949
  108. Agus DB, Cordon-Cardo C, Fox W, et al. Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst. 1999;91:1869–1876
  109. Guo Y, Sklar GN, Borkowski A, et al. Loss of the cyclin-dependent kinase inhibitor p27Kip1 protein in human prostate cancer correlates with tumor grade. Clin Cancer Res. 1997;3:2269–2274
  110. Tsihlias J, Kapusta LR, DeBoer G, et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 1998;58:542–548
  111. Cote RJ, Shi Y, Groshen S, et al. Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J Natl Cancer Inst. 1998;90:916–920
  112. De Marzo AM, Meeker AK, Epstein JI, et al. Prostate stem cell compartments: expression of the cell cycle inhibitor p27Kip1 in normal, hyperplastic, and neoplastic cells. Am J Pathol. 1998;153:911–919
  113. Yang RM, Naitoh J, Murphy M, et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol. 1998;159:941–945
  114. Kuczyk M, Machtens S, Hradil K, et al. Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer. 1999;81:1052–1058
  115. Kuczyk MA, Bokemeyer C, Hartmann J, et al. Predictive value of altered p27Kip1 and p21WAF/Cip1 protein expression for the clinical prognosis of patients with localized prostate cancer. Oncol Rep. 2001;8:1401–1407
  116. Cher ML, MacGrogan D, Bookstein R, et al. Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer. Genes, Chromosomes Cancer. 1994;11:153–162
  117. Cher ML, Bova GS, Moore DH, et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 1996;56:3091–3102
  118. Nupponen NN, Kakkola L, Koivisto P, et al. Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am J Pathol. 1998;153:141–148
  119. Sato K, Qian J, Slezak JM, et al. Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J Natl Cancer Inst. 1999;91:1574–1580
  120. Qian J, Jenkins RB, Bostwick DG. Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization. Mod Pathol. 1997;10:1113–1119
  121. Fox SB, Persad RA, Royds J, et al. p53 and c-myc expression in stage A1 prostatic adenocarcinoma: useful prognostic determinants?. J Urol. 1993;150:490–494
  122. Jenkins RB, Qian J, Lieber MM, et al. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res. 1997;57:524–531
  123. Bubendorf L, Kononen J, Koivisto P, et al. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays [published erratum appears in Cancer Res 1999;59(6):1388]. Cancer Res. 1999;59:803–806
  124. Buttyan R, Sawczuk IS, Benson MC, et al. Enhanced expression of the c-myc protooncogene in high-grade human prostate cancers. Prostate. 1987;11:327–337
  125. Fleming WH, Hamel A, MacDonald R, et al. Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Res. 1986;46:1535–1538
  126. Kirsch DG, Kastan MB. Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol. 1998;16:3158–3168
  127. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1–6
  128. Visakorpi T, Kallioniemi OP, Heikkinen A, et al. Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation. J Natl Cancer Inst. 1992;84:883–887
  129. Raffo AJ, Perlman H, Chen MW, et al. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res. 1995;55:4438–4445
  130. Bauer JJ, Sesterhenn IA, Mostofi FK, et al. Elevated levels of apoptosis regulator proteins p53 and bcl-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer. J Urol. 1996;156:1511–1516
  131. Apakama I, Robinson MC, Walter NM, et al. C. bcl-2 overexpression combined with p53 protein accumulation correlates with hormone-refractory prostate cancer. Br J Cancer. 1996;74:1258–1262
  132. Meyers FJ, Gumerlock PH, Chi SG, et al. Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors. Cancer. 1998;83:2534–2539
  133. Quinn DI, Henshall SM, Head D, et al. Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy. Cancer Res. 2000;60:1585–1594
  134. Stattin P, Westin P, Damber JE, et al. Short-term cellular effects induced by castration therapy in relation to clinical outcome in prostate cancer. Br J Cancer. 1998;77:670–675
  135. Rokhlin OW, Guseva N, Tagiyev A, et al. Bcl-2 oncoprotein protects the human prostatic carcinoma cell line PC3 from TRAIL-mediated apoptosis. Oncogene. 2001;20:2836–2843
  136. Agarwal ML, Taylor WR, Chernov MV, et al. The p53 network. J Biol Chem. 1998;273:1–4
  137. Liebermann DA, Hoffman B, Steinman RA. Molecular controls of growth arrest and apoptosis: p53-dependent and independent markers. Oncogene. 1995;11:199–210
  138. Dameron KM, Volpert OV, Tainsky MA, et al. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994;265:1582–1584
  139. Gasparini G, Weidner N, Bevilacqua P, et al. Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol. 1994;12:454–466
  140. Yu ED, Yu E, Meyer GE, et al. The relation of p53 protein nuclear accumulation and angiogenesis in human prostate cancer. Prostate Cancer Prostate Dis. 1997;1:39–44
  141. Mydlo JH, Kral JG, Volpe M, et al. An analysis of microvessel density, androgen receptor, p53 and HER-2/neu expression and Gleason score in prostate cancer. Preliminary results and therapeutic implications. Eur Urol. 1998;34:426–432
  142. Finlay CA, Hinds PW, Tan TH, et al. Activating mutations for transformation by p53 produce a gene product that forms an hsc 70-p 53 complex withan altered half-life. Mol Cell Biol. 1988;8:531–539
  143. Bartek J, Iggo R, Gannon J, et al. Genetic and immunochemical analysis of mutant p53 in human breast cacner cell lines. Oncogene. 1990;5:893–899
  144. Casey G, Lopez ME, Ramos JC, et al. DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies. Oncogene. 1996;13:1971–1981
  145. Bodner SM, Minna JD, Jensen SM, et al. Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation. Oncogene. 1992;7:743–749
  146. Melhem MF, Law JC, el-Ashmawy L, et al. Assessment of sensitivity and specificity of immunohistochemical staining of p53 in lung and head and neck cancers. Am J Pathol. 1995;146:1170–1177
  147. Midgley CA, Lane DP. p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. Oncogene. 1997;15:1179–1189
  148. Thor AD, Moore DH, Edgerton SM, et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992;84:845–855
  149. Elledge RM, Clark GM, Fuqua SA, et al. p53 protein accumulation detected by five different antibodies: relationship to prognosis and heat shock protein 70 in breast cancer. Cancer Res. 1994;54:3752–3757
  150. Xu H-J, Cagle PT, Hu S-X, et al. Altered retinoblastoma amd p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis. Clin Cancer Res. 1996;2:1169–1176
  151. Goh H-S, Yao J, Smith DR. p53 point mutation and survival in colorectal cancer patients. Cancer Res. 1995;55:5217–5221
  152. Grignon DJ, Caplan R, Sarkar FH, et al. p53 status and prognosis of locally advanced prostatic adenocarcinoma: a study based on RTOG 8610. J Natl Cancer Inst. 1997;89:158–165
  153. Kuczyk MA, Serth J, Bokemeyer C, et al. The prognostic value of p53 for long-term and recurrence-free survival following radical prostatectomy. Eur J Cancer. 1998;34:679–686
  154. Bauer JJ, Sesterhenn IA, Mostofi KF, et al. p53 nuclear protein expression is an independent prognostic marker in clinically localised prostate cancer patients undergoing radical prostatectomy. Clin Cancer Res. 1995;1:1295–1300
  155. Yang G, Stapleton AMF, Wheeler TM, et al. Clustered p53 immunostaining: a novel pattern associated with prostate cancer progression. Clin Cancer Res. 1996;2:399–401
  156. Brooks JD, Bova GS, Ewing CM, et al. An uncertain role for p53 gene alterations in human prostate cancers. Cancer Res. 1996;56:3814–3822
  157. Navone NM, Troncoso P, Pisters LL, et al. p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst. 1993;85:1657–1669
  158. Bookstein R, MacGrogan D, Hilsenbeck SG, et al. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Res. 1993;53:3369–3373
  159. Dinjens WN, van der Weiden MM, Schroeder FH, et al. Frequency and characterization of p53 mutations in primary and metastatic human prostate cancer. Int J Cancer. 1994;56:630–633
  160. Chi SG, deVere White RW, Meyers FJ, et al. p53 in prostate cancer: frequent expressed transition mutations. J Natl Cancer Inst. 1994;86:926–933
  161. Gumerlock PH, Chi SG, Shi XB, et al. p53 abnormalities in primary prostate cancer: single-strand conformation polymorphism analysis of complementary DNA in comparison with genomic DNA. The Cooperative Prostate Network. J Natl Cancer Inst. 1997;89:66–71
  162. Stapleton AMF, Timme TL, Gousse AE, et al. Primary human prostate cancer cells harboring p53 mutations are clonally expanded in metastases. Clin Cancer Res. 1997;3:1389–1397
  163. Bova GS. Molecular genetics of hormone refractory prostate cancer metastasis. In: Isaacs W, Nelso P, eds, Keystone Symposia: Breast and Prostate Cancer, Copper Mountain, CO; 1998 Keystone Symposia, Silverhorn, CO
  164. Suzuki H, Freije D, Nusskern DR, et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 1998;58:204–209
  165. Hughes JH, Cohen MB, Robinson RA. p53 immunoreactivity in primary and metastatic prostatic adenocarcinoma. Mod Pathol. 1995;8:462–466
  166. Eastham JA, Stapleton AMF, Gousse AE, et al. Association of p53 mutations with metastatic prostate cancer. Clin Cancer Res. 1995;1:1111–1118
  167. Rakozy C, Grignon DJ, Sarkar FH, et al. Expression of bcl-2, p53, and p21 in benign and malignant prostatic tissue before and after radiation therapy. Mod Pathol. 1998;11:892–899
  168. Prendergast NJ, Atkins MR, Schatte EC, et al. p53 immunohistochemical and genetic alterations are associated at high incidence with post-irradiated locally persistent prostate carcinoma. J Urol. 1996;155:1685–1692
  169. Mirchandani D, Zheng J, Miller GJ, et al. Heterogeneity in intratumor distribution of p53 mutations in human prostate cancer. Am J Pathol. 1995;147:92–101
  170. Konishi N, Hiasa Y, Matsuda H, et al. Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma. Am J Pathol. 1995;147:1112–1122
  171. Geburek BM, Kollmorgen TA, Qian J, et al. Chromosomal anomalies in stage D1 prostate adenocarcinoma primary tumors and lymph node metastases detected by fluorescence in situ hybridization. J Urol. 1997;157:223–227
  172. Qian J, Hirasawa K, Bostwick DG, et al. Loss of p53 and c-myc overrepresentation in stage T (2–3) N (1–3) M (0) prostate cancer are potential markers for cancer progression. Mod Pathol. 2002;15:35–44
  173. Griewe GL, Dean RC, Zhang W, et al. p53 Immunostaining guided laser capture microdissection (p53-LCM) defines the presence of p53 gene mutations in focal regions of primary prostate cancer positive for p53 protein. Prostate Cancer Prostatic Dis. 2003;6:281–285
  174. Borre M, Stausbol-Gron B, Overgaard J. p53 accumulation associated with bcl-2, the proliferation marker MIB-1 and survival in patients with prostate cancer subjected to watchful waiting. J Urol. 2000;164:716–721
  175. Haldar S, Beatty C, Tsujimoto Y, et al. The bcl-2 gene encodes a novel G protein. Nature. 1989;342:195–198
  176. Tsujimoto Y, Croce CM. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci USA. 1986;83:5214–5218
  177. McDonnell TJ, Troncoso P, Brisbay SM, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992;52:6940–6944
  178. Colombel M, Symmans F, Gil S, et al. Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. Am J Pathol. 1993;143:390–400
  179. Berchem GJ, Bosseler M, Sugars LY, et al. Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. Cancer Res. 1995;55:735–738
  180. McConkey DJ, Greene G, Pettaway CA. Apoptosis resistance increases with metastatic potential in cells of the human LNCaP prostate carcinoma line. Cancer Res. 1996;56:5594–5599
  181. Rosser CJ, Reyes AO, Vakar-Lopez F, et al. Bcl-2 is significantly overexpressed in localized radio-recurrent prostate carcinoma, compared with localized radio-naive prostate carcinoma. Int J Radiat Oncol Biol Phys. 2003;56:1–6
  182. Horvath LG, Henshall SM, Lee CS, et al. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res. 2001;61:5331–5335
  183. Gorelic LS, Lamm DL, Ramzy I, et al. Androgen receptors in biopsy specimens of prostate adenocarcinoma. Heterogeneity of distribution and relation to prognostic significance of receptor measurements for survival of advanced cancer patients. Cancer. 1987;60:211–219
  184. de Winter JA, Trapman J, Brinkmann AO, et al. Androgen receptor heterogeneity in human prostatic carcinomas visualized by immunohistochemistry. J Pathol. 1990;160:329–332
  185. Sadi MV, Barrack ER. Androgen receptors and growth fraction in metastatic prostate cancer as predictors of time to tumour progression after hormonal therapy. Cancer Surv. 1991;11:195–215
  186. van der Kwast TH, Schalken J, Ruizeveld de Winter JA, et al. Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer. 1991;48:189–193
  187. Chodak GW, Kranc DM, Puy LA, et al. Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. J Urol. 1992;147:798–803
  188. Miyamoto KK, McSherry SA, Dent GA, et al. Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue. J Urol. 1993;149:1015–1019
  189. Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, et al. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol. 1994;144:735–746
  190. Magi-Galluzzi C, Xu X, Hlatky L, et al. Heterogeneity of androgen receptor content in advanced prostate cancer. Mod Pathol. 1997;10:839–845
  191. Tilley WD, Lim-Tio SS, Horsfall DJ, et al. Detection of discrete androgen receptor epitopes in prostate cancer by immunostaining: measurement by color video image analysis. Cancer Res. 1994;54:4096–4102
  192. Peterziel H, Culig Z, Stober J, et al. Mutant androgen receptors in prostatic tumors distinguish between amino-acid-sequence requirements for transactivation and ligand binding. Int J Cancer. 1995;63:544–550
  193. Hobisch A, Culig Z, Radmayr C, et al. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res. 1995;55:3068–3072
  194. Prins GS, Sklarew RJ, Pertschuk LP. Image analysis of androgen receptor immunostaining in prostate cancer accurately predict response to hormonal therapy. J Urol. 1998;159:641–649
  195. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314–319
  196. Koivisto P, Kolmer M, Visakorpi T, et al. Androgen receptor gene and hormonal therapy failure of prostate cancer. Am J Pathol. 1998;152:1–9
  197. Olapade-Olaopa EO, MacKay EH, Taub NA, et al. Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. Clin Cancer Res. 1999;5:569–576
  198. Takeda H, Akakura K, Masai M, et al. Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer. 1996;77:934–940
  199. Sweat SD, Pacelli A, Bergstralh EJ, et al. Androgen receptor expression in prostate cancer lymph node metastases is predictive of outcome after surgery. J Urol. 1999;161:1233–1237
  200. Sweat SD, Pacelli A, Bergstralh EJ, et al. Androgen receptor expression in prostatic intraepithelial neoplasia and cancer. J Urol. 1999;161:1229–1232
  201. Wilson CM, Griffin JE, Wilson JD, et al. Immunoreactive androgen receptor expression in subjects with androgen resistance. J Clin Endocrinol Metab. 1992;75:1474–1478
  202. Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–406
  203. Olumi AF, Grossfeld GD, Hayward SW, et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002–5011
  204. Koivisto P, Hyytinen E, Palmberg C, et al. Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy. Am J Pathol. 1995;147:1608–1614
  205. Henshall SM, Quinn DI, Lee CS, 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;61:423–427
  206. Wolf DA, Herzinger T, Hermeking H, et al. Transcriptional and posttranscriptional regulation of human androgen receptor expression by androgen. Mol Endocrinol. 1993;7:924–936
  207. Thompson TC, Timme TL, Kadmon D, et al. Genetic predisposition and mesenchymal–epithelial interactions in ras+myc-induced carcinogenesis in reconstituted mouse prostate. Mol Carcinog. 1993;7:165–179
  208. Lee C, Sintich SM, Mathews EP, et al. Transforming growth factor-beta in benign and malignant prostate. Prostate. 1999;39:285–290
  209. Kooistra A, Romijn JC, Schroder FH. Stromal inhibition of epithelial cell growth in the prostate; overview of an experimental study. Urol Res. 1997;25(Suppl. 2):S97–S105
  210. Gleave M, Hsieh JT, Gao CA, et al. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res. 1991;51:3753–3761
  211. Planz B, Wang Q, Kirley SD, et al. Androgen responsiveness of stromal cells of the human prostate: regulation of cell proliferation and keratinocyte growth factor by androgen. J Urol. 1998;160:1850–1855
  212. Lu W, Luo Y, Kan M, et al. Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate [published erratum appears in J Biol Chem 1999;274(39):28058]. J Biol Chem. 1999;274:12827–12834
  213. Hobisch A, Eder IE, Putz T, et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 1998;58:4640–4645
  214. Gerdes MJ, Dang TD, Larsen M, et al. Transforming growth factor-beta1 induces nuclear to cytoplasmic distribution of androgen receptor and inhibits androgen response in prostate smooth muscle cells. Endocrinology. 1998;139:3569–3577
  215. Leung HY, Mehta P, Gray LB, et al. Keratinocyte growth factor expression in hormone insensitive prostate cancer. Oncogene. 1997;15:1115–1120
  216. Kattan MW, Shariat SF, Andrews B, et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol. 2003;21:3573–3579
  217. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–1398
  218. Veldscholte J, Ris-Stalpers C, Kuiper GG, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990;173:534–540
  219. Veldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41:665–669
  220. Suzuki H, Akakura K, Komiya A, et al. Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate. 1996;29:153–158
  221. Fenton MA, Shuster TD, Fertig AM, et al. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res. 1997;3:1383–1388
  222. Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999;59:2511–2515
  223. Palmberg C, Koivisto P, Hyytinen E, et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur Urol. 1997;31:216–219
  224. Tilley WD, Buchanan G, Hickey TE, et al. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clinical Cancer Res. 1996;2:277–286
  225. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7:1541–1550
  226. Gaddipati JP, McLeod DG, Heidenberg HB, et al. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res. 1994;54:2861–2864
  227. Elo JP, Kvist L, Leinonen K, et al. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol. J Clin Endocrinol Metab. 1995;80:3494–3500
  228. Bentel JM, Tilley WD. Androgen receptors in prostate cancer. J Endocrinol. 1996;151:1–11
  229. Choong CS, Sturm MJ, Strophair JA, et al. Partial androgen insensitivity caused by an androgen receptor mutation at amino acid 907 (Gly–>Arg) that results in decreased ligand binding affinity and reduced androgen receptor messenger ribonucleic acid levels. J Clin Endocrinol Metab. 1996;81:236–243
  230. Tan J, Sharief Y, Hamil KG, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997;11:450–459
  231. Craft N, Shostak Y, Carey M, et al. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280–285
  232. Yeh S, Lin HK, Kang HY, et al. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA. 1999;96:5458–5463
  233. Lu J, Danielsen M. Differential regulation of androgen and glucocorticoid receptors by retinoblastoma protein. J Biol Chem. 1998;273:31528–31533
  234. Koivisto PA, Rantala I. Amplification of the androgen receptor gene is associated with P53 mutation in hormone-refractory recurrent prostate cancer. J Pathol. 1999;187:237–241
  235. Jia L, Choong CS, Ricciardelli C, et al. Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res. 2004;64:2619–2626
  236. Lee SO, Lou W, Hou M, et al. Interleukin-4 enhances prostate-specific antigen expression by activation of the androgen receptor and Akt pathway. Oncogene. 2003;22:7981–7988
  237. Bernard D, Pourtier-Manzanedo A, Gil J, et al. Myc confers androgen-independent prostate cancer cell growth. J Clin Invest. 2003;112:1724–1731
  238. Jenster G. The role of the androgen receptor in the development and progression of prostate cancer. Semin Oncol. 1999;26:407–421
  239. Bonkhoff H, Stein U, Aumuller G, et al. Differential expression of 5 alpha-reductase isoenzymes in the human prostate and prostatic carcinomas. Prostate. 1996;29:261–267
  240. Myers RB, Srivastava S, Oelschlager DK, et al. Expression of p160erbB-3 and p185erbB-2 in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. J Natl Cancer Inst. 1994;86:1140–1145
  241. Myers RB, Brown D, Oelschlager DK, et al. Elevated serum levels of p105 (erbB-2) in patients with advanced-stage prostatic adenocarcinoma. Int J Cancer. 1996;69:398–402
  242. Scher HI, Sarkis A, Reuter V, et al. Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. Clin Cancer Res. 1995;1:545–550
  243. Ye D, Mendelsohn J, Fan Z. Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. Clin Cancer Res. 1999;5:2171–2177
  244. Ross JS, Nazeer T, Church K, et al. Contribution of HER-2/neu oncogene expression to tumor grade and DNA content analysis in the prediction of prostatic carcinoma metastasis. Cancer. 1993;72:3020–3028
  245. Kuhn EJ, Kurnot RA, Sesterhenn IA, et al. Expression of the c-erbB-2 (HER-2/neu) oncoprotein in human prostatic carcinoma. J Urol. 1993;150:1427–1433
  246. Fox SB, Persad RA, Coleman N, et al. Prognostic value of c-erbB-2 and epidermal growth factor receptor in stage A1 (T1a) prostatic adenocarcinoma. Br J Urol. 1994;74:214–220
  247. Kallakury BV, Sheehan CE, Ambros RA, et al. Correlation of p34cdc2 cyclin-dependent kinase overexpression, CD44s downregulation, and HER-2/neu oncogene amplification with recurrence in prostatic adenocarcinomas. J Clin Oncol. 1998;16:1302–1309
  248. Visakorpi T. New pieces to the prostate puzzle. Nature Med. 1999;5:264–265
  249. Mark HF, Feldman D, Das S, et al. Fluorescence in situ hybridization study of HER-2/neu oncogene amplification in prostate cancer. Exp Mol Pathol. 1999;66:170–178
  250. Morote J, de Torres I, Caceres C, et al. Prognostic value of immunohistochemical expression of the c-erbB-2 oncoprotein in metastasic prostate cancer. Int J Cancer. 1999;84:421–425
  251. Lara PN, Chee KG, Longmate J, et al. Trastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma: final results from the California Cancer Consortium Screening and Phase II Trial. Cancer. 2004;100:2125–2131
  252. Visakorpi T, Kallioniemi OP, Koivula T, et al. Expression of epidermal growth factor receptor and ERBB2 (HER-2/Neu) oncoprotein in prostatic carcinomas. Mod Pathol. 1992;5:643–648
  253. Mellon K, Thompson S, Charlton RG, et al. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate. J Urol. 1992;147:496–499
  254. Robinson D, He F, Pretlow T, et al. A tyrosine kinase profile of prostate carcinoma. Proc Natl Acad Sci USA. 1996;93:5958–5962
  255. Lu X, Park SH, Thompson TC, et al. Ras-induced hyperplasia occurs with mutation of p53, but activated ras and myc together can induce carcinoma without p53 mutation. Cell. 1992;70:153–161
  256. Thompson TC, Park SH, Timme TL, et al. Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene. 1995;10:869–879
  257. Fan K. Heterogeneous subpopulations of human prostatic adenocarcinoma cells: potential usefulness of P21 protein as a predictor for bone metastasis. J Urol. 1988;139:318–322
  258. Peehl DM, Wehner N, Stamey TA. Activated Ki-ras oncogene in human prostatic adenocarcinoma. Prostate. 1987;10:281–289
  259. Moul JW, Friedrichs PA, Lance RS, et al. Infrequent RAS oncogene mutations in human prostate cancer. Prostate. 1992;20:327–338
  260. Watanabe M, Shiraishi T, Yatani R, et al. International comparison on ras gene mutations in latent prostate carcinoma. Intl J Cancer. 1994;58:174–178
  261. Bushman EC, Nayak RN, Bushman W. Immunohistochemical staining of ras p21: staining in benign and malignant prostate tissue. J Urol. 1995;153:233–237
  262. Konishi N, Hiasa Y, Tsuzuki T, et al. Comparison of ras activation in prostate carcinoma in Japanese and American men. Prostate. 1997;30:53–57
  263. Shiraishi T, Muneyuki T, Fukutome K, et al. Mutations of ras genes are relatively frequent in Japanese prostate cancers: pointing to genetic differences between populations. Anticancer Res. 1998;18:2789–2792
  264. Ramaswamy S, Nakamura N, Vazquez F, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1999;96:2110–2115
  265. Graff JR, Konicek BW, McNulty AM, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000;275:24500–24505
  266. Liang J, Zubovitz J, Petrocelli T, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153–1160
  267. Radu A, Neubauer V, Akagi T, et al. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol. 2003;23:6139–6149
  268. Tolcher AW. Novel therapeutic molecular targets for prostate cancer: the mTOR signaling pathway and epidermal growth factor receptor. J Urol. 2004;171:S41–S43(discussion S44)
  269. Majumder PK, Yeh JJ, George DJ, et al. Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci USA. 2003;100:7841–7846
  270. Wang S, Gao J, Lei Q, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4:209–221
  271. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–1947
  272. Cairns P, Okami K, Halachmi S, et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 1997;57:4997–5000
  273. Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA. 1998;95:5246–5250
  274. Wu X, Senechal K, Neshat MS, et al. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1998;95:15587–15591
  275. McMenamin ME, Soung P, Perera S, et al. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999;59:4291–4296
  276. Huang H, Cheville JC, Pan Y, et al. PTEN induces chemosensitivity in pten-mutated prostate cancer cells by suppression of bcl-2 expression. J Biol Chem. 2001;276:38830–38836
  277. Nan B, Snabboon T, Unni E, et al. The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. J Mol Endocrinol. 2003;31:169–183
  278. Edwards J, Krishna NS, Witton CJ, et al. Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin Cancer Res. 2003;9:5271–5281
  279. Liao Y, Grobholz R, Abel U, et al. Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer. Int J Cancer. 2003;107:676–680
  280. Malik SN, Brattain M, Ghosh PM, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res. 2002;8:1168–1171
  281. Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991;251:1451–1455
  282. Steinberg MS, Takeichi M. Experimental specification of cell sorting, tissue spreading, and specific spatial patterning by quantitative differences in cadherin expression. Proc Natl Acad Sci USA. 1994;91:206–209
  283. Shimoyama Y, Nagafuchi A, Fujita S, et al. Cadherin dysfunction in a human cancer cell line: possible involvement of loss of alpha-catenin expression in reduced cell–cell adhesiveness. Cancer Res. 1992;52:5770–5774
  284. Hirano S, Kimoto N, Shimoyama Y, et al. Identification of a neural alpha-catenin as a key regulator of cadherin function and multicellular organization. Cell. 1992;70:293–301
  285. Umbas R, Schalken JA, Aalders TW, et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res. 1992;52:5104–5109
  286. Richmond PJ, Karayiannakis AJ, Nagafuchi A, et al. Aberrant E-cadherin and alpha-catenin expression in prostate cancer: correlation with patient survival. Cancer Res. 1997;57:3189–3193
  287. Aaltomaa S, Lipponen P, Ala-Opas M, et al. Alpha-catenin expression has prognostic value in local and locally advanced prostate cancer. Br J Cancer. 1999;80:477–482
  288. Umbas R, Isaacs WB, Bringuier PP, et al. Relation between aberrant alpha-catenin expression and loss of E-cadherin function in prostate cancer. Int J Cancer. 1997;74:374–377
  289. Cheng L, Nagabhushan M, Pretlow TP, et al. Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol. 1996;148:1375–1380
  290. Tomita K, van Bokhoven A, van Leenders GJ, et al. Cadherin switching in human prostate cancer progression. Cancer Res. 2000;60:3650–3654
  291. Bussemakers MJ, Van Bokhoven A, Tomita K, et al. Complex cadherin expression in human prostate cancer cells. Int J Cancer. 2000;85:446–450
  292. De Marzo AM, Knudsen B, Chan-Tack K, et al. E-cadherin expression as a marker of tumor aggressiveness in routinely processed radical prostatectomy specimens. Urology. 1999;53:707–713
  293. Bryden AA, Freemont AJ, Clarke NW, et al. Paradoxical expression of E-cadherin in prostatic bone metastases. BJU Int. 1999;84:1032–1034
  294. Bukholm IK, Nesland JM, Borresen-Dale AL. Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients. J Pathol. 2000;190:15–19
  295. Kuniyasu H, Ukai R, Johnston D, et al. The relative mRNA expression levels of matrix metalloproteinase to E-cadherin in prostate biopsy specimens distinguishes organ-confined from advanced prostate cancer at radical prostatectomy. Clin Cancer Res. 2003;9:2185–2194
  296. Kuefer R, Hofer MD, Gschwend JE, et al. The role of an 80kDa fragment of E-cadherin in the metastatic progression of prostate cancer. Clin Cancer Res. 2003;9:6447–6452
  297. Rashid MG, Sanda MG, Vallorosi CJ, et al. Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate. Cancer Res. 2001;61:489–492
  298. Sasaki CY, Lin H, Morin PJ, et al. Truncation of the extracellular region abrogrates cell contact but retains the growth-suppressive activity of E-cadherin. Cancer Res. 2000;60:7057–7065
  299. Rios-Doria J, Day KC, Kuefer R, et al. The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells. J Biol Chem. 2003;278:1372–1379
  300. Rhodes DR, Sanda MG, Otte AP, et al. Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. J Natl Cancer Inst. 2003;95:661–668
  301. Ruijter E, van de Kaa C, Aalders T, et al. Heterogeneous expression of E-cadherin and p53 in prostate cancer: clinical implications. BIOMED-II Markers for Prostate Cancer Study Group. Mod Pathol. 1998;11:276–281
  302. Brewster SF, Oxley JD, Trivella M, et al. Preoperative p53, bcl-2, CD44 and E-cadherin immunohistochemistry as predictors of biochemical relapse after radical prostatectomy. J Urol. 1999;161:1238–1243
  303. Nusse R, Varmus HE. Wnt genes. Cell. 1992;69:1073–1087
  304. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;
  305. Miller JR. The Wnts. Genome Biol. 2002;3:3001;(reviews)
  306. Iozzo RV, Eichstetter I, Danielson KG. Aberrant expression of the growth factor Wnt-5A in human malignancy. Cancer Res. 1995;55:3495–3499
  307. Wissmann C, Wild PJ, Kaiser S, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol. 2003;201:204–212
  308. Sagara N, Toda G, Hirai M, et al. Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7. Biochem Biophys Res Commun. 1998;252:117–122
  309. Chesire DR, Ewing CM, Gage WR, et al. In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene. 2002;21:2679–2694
  310. de la Taille A, Rubin MA, Chen MW, et al. Beta-catenin-related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells. Clin Cancer Res. 2003;9:1801–1807
  311. Chen G, Shukeir N, Potti A, et al. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer. 2004;101:1345–1356
  312. Horvath LG, Henshall SM, Lee CS, et al. Loss of nuclear beta-catenin predicts for a poorer prognosis in localized prostate cancer. Int J Cancer. 2005;113:415–422
  313. Horvath LG, Henshall SM, Kench JG, et al. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res. 2004;10:615–625
  314. Mulholland DJ, Read JT, Rennie PS, et al. Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis. Oncogene. 2003;22:5602–5613
  315. Damalas A, Ben-Ze’ev A, Simcha I, et al. Excess beta-catenin promotes accumulation of transcriptionally active p53. EMBO J. 1999;18:3054–3063
  316. Sasaki T, Suzuki H, Yagi K, et al. Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc. Cancer Res. 2003;63:801–806
  317. Ricciardelli C, Quinn DI, Raymond WA, et al. Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer. Cancer Res. 1999;59:2324–2328
  318. Ricciardelli C, Mayne K, Sykes PJ, et al. Elevated levels of versican but not decorin predict disease progression in early-stage prostate cancer. Clin Cancer Res. 1998;4:963–971
  319. Ricciardelli C, Mayne K, Sykes PJ, et al. Elevated stromal chondroitin sulfate glycoaminoglycan predicts progression in early stage prostate cancer. Clin Cancer Res. 1997;3:983–992
  320. Nelson PS, Plymate SR, Wang K, et al. Hevin, an antiadhesive extracellular matrix protein, is down-regulated in metastatic prostate adenocarcinoma. Cancer Res. 1998;58:232–236
  321. Noordzij MA, van Steenbrugge GJ, Schroder FH, et al. Decreased expression of CD44 in metastatic prostate cancer. Int J Cancer. 1999;84:478–483
  322. Jackson MW, Bentel JM, Tilley WD. Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol. 1997;157:2323–2328
  323. Silberman MA, Partin AW, Veltri RW, et al. Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate. Cancer. 1997;79:772–779
  324. Weidner N, Carroll PR, Flax J, et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993;143:401–409
  325. Borre M, Offersen BV, Nerstrom B, et al. Microvessel density predicts survival in prostate cancer patients subjected to watchful waiting. Br J Cancer. 1998;78:940–944
  326. Borre M, Nerstrom B, Overgaard J. Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. Clin Cancer Res. 2000;6:1882–1890
  327. Strohmeyer D, Rossing C, Bauerfeind A, et al. Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer. Prostate. 2000;45:216–224
  328. Fernandez A, Udagawa T, Schwesinger C, et al. Angiogenic potential of prostate carcinoma cells overexpressing bcl-2. J Natl Cancer Inst. 2001;93:208–213
  329. Ferrer FA, Miller LJ, Andrawis A, et al. Angiogenesis and prostate cancer: in vivo and in vitro expression of angiogenesis factors by prostate cancer cells. Urology. 1998;51:161–167
  330. Mabjeesh NJ, Willard MT, Frederickson CE, et al. Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 3prime-kinase/protein kinase B in prostate cancer cells. Clin Cancer Res. 2003;9:2416–2425
  331. Kuniyasu H, Troncoso P, Johnston D, et al. Relative expression of type IV collagenae, E-cadherin, and vascular endothelial growth factor/vascular permeability factor in prostatectomy specimens distinguishes organ-confined from pathologically advanced prostate cancers. Clin Cancer Res. 2000;6:2295–2308
  332. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–844
  333. Joseph IB, Nelson JB, Denmeade SR, et al. Androgens regulate vascular endothelial growth factor content in normal and malignant prostatic tissue. Clin Cancer Res. 1997;3:2507–2511
  334. Stewart RJ, Panigrahy D, Flynn E, et al. Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol. 2001;165:688–693
  335. Sordello S, Bertrand N, Plouet J. Vascular endothelial growth factor is up-regulated in vitro and in vivo by androgens. Biochem Biophys Res Commun. 1998;251:287–290
  336. Miao HQ, Lee P, Lin H, et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. Faseb J. 2000;14:2532–2539
  337. Richard C, Kim G, Koikawa Y, et al. Androgens modulate the balance between VEGF and angiopoietin expression in prostate epithelial and smooth muscle cells. Prostate. 2002;50:83–91
  338. Gagnon ML, Bielenberg DR, Gechtman Z, et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: in vivo expression and antitumor activity. Proc Natl Acad Sci USA. 2000;97:2573–2578
  339. Ruiz M, Pettaway C, Song R, et al. Activator protein 2a inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells. Cancer Res. 2004;64:631–638
  340. Levine L, Lucci JA, Pazdrak B, et al. Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res. 2003;63:3495–3502
  341. Ferrer FA, Miller LJ, Andrawis RI, et al. Vascular endothelial growth factor (VEGF) expression in human prostate cancer: in situ and in vitro expression of VEGF by human prostate cancer cells. J Urol. 1997;157:2329–2333
  342. Mazzucchelli R, Montironi R, Santinelli A, et al. Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients. Prostate. 2000;45:72–79
  343. Chevalier S, Defoy I, Lacoste J, et al. Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis. Mol Cell Endocrinol. 2002;189:169–179
  344. Harper ME, Glynne-Jones E, Goddard L, et al. Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells. Br J Cancer. 1996;74:910–916
  345. Ismail AH, Altaweel W, Chevalier S, et al. Expression of vascular endothelial growth factor-A in human lymph node metastases of prostate cancer. Can J Urol. 2004;11:2146–2150
  346. George DJ, Halabi S, Shepard TF, et al. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res. 2001;7:1932–1936
  347. Small EJ, Meyer M, Marshall ME, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000;18:1440–1450
  348. Chan LW, Moses MA, Goley E, et al. Urinary VEGF and MMP levels as predictive markers of 1-year progression-free survival in cancer patients treated with radiation therapy: a longitudinal study of protein kinetics throughout tumor progression and therapy. J Clin Oncol. 2004;22:499–506
  349. Shariat SF, Anwuri VA, Lamb DJ, et al. Association of preoperative plasma levels of vascular endothelial growth factor and soluble vascular cell adhesion molecule-1 with lymph node status and biochemical progression after radical prostatectomy. J Clin Oncol. 2004;22:1655–1663
  350. George DJ, Regan MM, Oh WK, et al. Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer. Urology. 2004;63:327–332
  351. Kohli M, Kaushal V, Spencer HJ, et al. Prospective study of circulating angiogenic markers in prostate-specific antigen (PSA)-stable and PSA-progressive hormone-sensitive advanced prostate cancer. Urology. 2003;61:765–769
  352. Figg WD, Kruger EA, Price DK, et al. Inhibition of angiogenesis: treatment options for patients with metastatic prostate cancer. Invest New Drugs. 2002;20:183–194
  353. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611
  354. Kollermann J, Helpap B. Expression of vascular endothelial growth factor (VEGF) and VEGF receptor Flk-1 in benign, premalignant, and malignant prostate tissue. Am J Clin Pathol. 2001;116:115–121
  355. Kearney JB, Kappas NC, Ellerstrom C, et al. The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood. 2004;103:4527–4535
  356. Elkin M, Orgel A, Kleinman HK. An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst. 2004;96:875–878
  357. Shimizu K, Kubo H, Yamaguchi K, et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004;95:328–333
  358. Jackson MW, Roberts JS, Heckford SE, et al. A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res. 2002;62:854–859
  359. Sweeney P, Karashima T, Kim SJ, et al. Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production. Clin Cancer Res. 2002;8:2714–2724
  360. Huss WJ, Hanrahan CF, Barrios RJ, et al. Angiogenesis and prostate cancer: identification of a molecular progression switch. Cancer Res. 2001;61:2736–2743
  361. Dai J, Kitagawa Y, Zhang J, et al. Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. Cancer Res. 2004;64:994–999
  362. Li R, Younes M, Wheeler TM, et al. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate. 2004;58:193–199
  363. Zeng Y, Opeskin K, Baldwin ME, et al. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res. 2004;10:5137–5144
  364. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–10874
  365. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–536
  366. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009
  367. Singh D, Febbo PG, Ross K, et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 2002;1:203–209
  368. Lapointe J, Li C, Higgins JP, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA. 2004;101:811–816
  369. Kirdani RY, Emrich LJ, Pontes EJ, et al. A comparison of estrogen and androgen receptor levels in human prostatic tissue from patients with non-metastatic and metastatic carcinoma and benign prostatic hyperplasia. J Steroid Biochem. 1985;22:569–575
  370. Umbas R, Isaacs WB, Bringuier PP, et al. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res. 1994;54:3929–3933
  371. Morita N, Uemura H, Tsumatani K, et al. E-cadherin and alpha-, beta- and gamma-catenin expression in prostate cancers: correlation with tumour invasion. Br J Cancer. 1999;79:1879–1883
  372. Wood M, Fudge K, Mohler JL, et al. In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin Exp Metastasis. 1997;15:246–258
  373. Luo J, Lubaroff DM, Hendrix MJ. Suppression of prostate cancer invasive potential and matrix metalloproteinase activity by E-cadherin transfection. Cancer Res. 1999;59:3552–3556
  374. Sanchez-Sweatman OH, Orr FW, Singh G. Human metastatic prostate PC3 cell lines degrade bone using matrix metalloproteinases. Invasion Metastasis. 1998;18:297–305
  375. Ge K, Minhas F, Duhadaway J, et al. Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. Int J Cancer. 2000;86:155–161
  376. Cooney KA, Wetzel JC, Consolino CM, et al. Identification and characterization of proximal 6q deletions in prostate cancer. Cancer Res. 1996;56:4150–4153
  377. Alers JC, Krijtenburg PJ, Vissers KJ, et al. Interphase cytogenetics of prostatic adenocarcinoma and precursor lesions: analysis of 25 radical prostatectomies and 17 adjacent prostatic intraepithelial neoplasias. Genes, Chromosomes & Cancer. 1995;12:241–250
  378. Trapman J, Sleddens HF, van der Weiden MM, et al. Loss of heterozygosity of chromosome 8 microsatellite loci implicates a candidate tumor suppressor gene between the loci D8S87 and D8S133 in human prostate cancer. Cancer Res. 1994;54:6061–6064
  379. Emmert-Buck MR, Vocke CD, Pozzatti RO, et al. Allelic loss on chromosome 8p12-21 in microdissected prostatic intraepithelial neoplasia. Cancer Res. 1995;55:2959–2962
  380. Vocke CD, Pozzatti RO, Bostwick DG, et al. Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12–21. Cancer Res. 1996;56:2411–2416
  381. Bova GS, MacGrogan D, Levy A, et al. Physical mapping of chromosome 8p22 markers and their homozygous deletion in a metastatic prostate cancer. Genomics. 1996;35:46–54
  382. Bova GS, Carter BS, Bussemakers MJ, et al. Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in human prostate cancer. Cancer Res. 1993;53:3869–3873
  383. Cabeza-Arvelaiz Y, Thompson TC, Sepulveda JL, et al. LAPSER1: a novel candidate tumor suppressor gene from 10q24.3. Oncogene. 2001;20:6707–6717
  384. Ishii H, Baffa R, Numata SI, et al. The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. Proc Natl Acad Sci USA. 1999;96:3928–3933
  385. Tsuchiya N, Kondo Y, Takahashi A, et al. Mapping and gene expression profile of the minimally overrepresented 8q24 region in prostate cancer. Am J Pathol. 2002;160:1799–1806
  386. Kaltz-Wittmer C, Klenk U, Glaessgen A, et al. FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy. Lab Invest. 2000;80:1455–1464
  387. Perinchery G, Bukurov N, Nakajima K, et al. High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer. Int J Cancer. 1999;83:610–614
  388. Narla G, Heath KE, Reeves HL, et al. KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science. 2001;294:2563–2566
  389. Fukuhara H, Maruyama T, Nomura S, et al. Functional evidence for the presence of tumor suppressor gene on chromosome 10p15 in human prostate cancers. Oncogene. 2001;20:314–319
  390. Carter BS, Ewing CM, Ward WS, et al. Allelic loss of chromosomes 16q and 10q in human prostate cancer. Proc Natl Acad Sci USA. 1990;87:8751–8755
  391. Matsuyama H, Pan Y, Yoshihiro S, et al. Clinical significance of chromosome 8p, 10q, and 16q deletions in prostate cancer. Prostate. 2003;54:103–111
  392. Srivastava M, Bubendorf L, Srikantan V, et al. ANX7, a candidate tumor suppressor gene for prostate cancer. Proc Natl Acad Sci USA. 2001;98:4575–4580
  393. Feilotter HE, Nagai MA, Boag AH, et al. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene. 1998;16:1743–1748
  394. Rubin MA, Gerstein A, Reid K, et al. 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer. Hum Pathol. 2000;31:504–508
  395. Latil A, Morant P, Fournier G, et al. CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer. Int J Cancer. 2002;99:689–696
  396. Cher ML, Ito T, Weidner N, et al. Mapping of regions of physical deletion on chromosome 16q in prostate cancer cells by fluorescence in situ hybridization (FISH). J Urol. 1995;153:249–254
  397. Berges RR, Vukanovic J, Epstein JI, et al. Implication of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res. 1995;1:473–480
  398. Matsushima H, Goto T, Hosaka Y, et al. Correlation between proliferation, apoptosis, and angiogenesis in prostate carcinoma and their relation to androgen ablation. Cancer. 1999;85:1822–1827
  399. Westin P, Stattin P, Damber JE, et al. Castration therapy rapidly induces apoptosis in a minority and decreases cell proliferation in a majority of human prostatic tumors. Am J Pathol. 1995;146:1368–1375
  400. Theodorescu D, Broder SR, Boyd JC, et al. p53, bcl-2 and retinoblastoma proteins as long-term prognostic markers in localized carcinoma of the prostate. J Urol. 1997;158:131–137
  401. Aaltomaa S, Lipponen P, Eskelinen M, et al. Prognostic value and expression of p21 (waf1/cip1) protein in prostate cancer. Prostate. 1999;39:8–15
  402. Matsushima H, Sasaki T, Goto T, et al. Immunohistochemical study of p21WAF1 and p53 proteins in prostatic cancer and their prognostic significance. Hum Pathol. 1998;29:778–783
  403. Cheville JC, Lloyd RV, Sebo TJ, et al. Expression of p27kip1 in prostatic adenocarcinoma. Mod Pathol. 1998;11:324–328
  404. Erdamar S, Yang G, Harper JW, et al. Levels of expression of p27KIP1 protein in human prostate and prostate cancer: an immunohistochemical analysis. Mod Pathol. 1999;12:751–755
  405. Borre M, Stausbol-Gron B, Nerstrom B, et al. Immunohistochemical BCL-2 and Ki-67 expression predict survival in prostate cancer patients followed expectantly. Prostate Cancer Prostatic Dis. 1998;1:268–275
  406. Borre M, Nerstrom B, Overgaard J. The natural history of prostate carcinoma based on a Danish population treated with no intent to cure. Cancer. 1997;80:917–928
  407. Stackhouse GB, Sesterhenn IA, Bauer JJ, et al. p53 and bcl-2 immunohistochemistry in pretreatment prostate needle biopsies to predict recurrence of prostate cancer after radical prostatectomy. J Urol. 1999;162:2040–2045
  408. Scherr DS, Vaughan ED, Wei J, et al. BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy [published erratum appears in J Urol 1999;162(2):503]. J Urol. 1999;162:12–16
  409. Kuczyk M, Serth J, Machtens S, et al. Expression of E-cadherin in primary prostate cancer: correlation with clinical features. Br J Urol. 1998;81:406–412
  410. Ross JS, Figge HL, Bui HX, et al. E-cadherin expression in prostatic carcinoma biopsies: correlation with tumor grade, DNA content, pathologic stage, and clinical outcome. Mod Pathol. 1994;7:835–841
  411. Magee JA, Araki T, Patil S, et al. Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Res. 2001;61:5692–5696
  412. Dhanasekaran SM, Barrette TR, Ghosh D, et al. Delineation of prognostic biomarkers in prostate cancer. Nature. 2001;412:822–826
  413. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–629
  414. Hofer MD, Kuefer R, Varambally S, et al. The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res. 2004;64:825–829
  415. Loda M, Fogt F, French FS, et al. Androgen receptor immunohisto chemistry on paraffin-embedded tissue. Med Pathol. 1994;7(3):388–391

PII: S0959-8049(05)00147-4

doi: 10.1016/j.ejca.2004.12.035

European Journal of Cancer
Volume 41, Issue 6 , Pages 858-887 , April 2005