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Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

Oncogene volume 29, pages 3593–3604 (2010)Cite this article

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Abstract

Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells.

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References

  • Agarwal PK, Oefelein MG . (2005). Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 173: 533–536.

    Article  CAS  PubMed  Google Scholar 

  • Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD . (1993). Effect of intermittent androgen-suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer 71: 2782–2790.

    Article  CAS  PubMed  Google Scholar 

  • Altuwaijri S, Wu CC, Niu YJ, Mizokami A, Chang HC, Chang C . (2007). Expression of human AR cDNA driven by its own promoter results in mild promotion, but of suppression, of growth in human prostate cancer PC-3 cells. Asian J Androl 9: 181–188.

    Article  CAS  PubMed  Google Scholar 

  • Anderson KM, Liao S . (1968). Selective retention of dihydrotestosterone by prostatic nuclei. Nature 219: 277–279.

    Article  CAS  PubMed  Google Scholar 

  • Banach-Petrosky W, Jessen WJ, Ouyang X, Gao H, Rao J, Quinn J et al. (2007). Prologed exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res 67: 9089–9096.

    Article  CAS  PubMed  Google Scholar 

  • Baritaki S, Chapman A, Yeung K, Spandiidos DA, Palladino M, Bonavida B . (2009). Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene 28: 3573–3585.

    Article  CAS  PubMed  Google Scholar 

  • Basaria S . (2008). Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: an inconvenient truth. J Androl 29: 534–539.

    Article  PubMed  Google Scholar 

  • Bhatia B, Tang S, Yang P, Doll A, Auműeller G, Newman RA et al. (2005). Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells. Oncogene 24: 3583–3595.

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick NA, Moses HL . (2005). Tumor-stroma interactions. Curr Opin Genet Develop 15: 97–101.

    Article  CAS  Google Scholar 

  • Bouzin C, Feron O . (2007). Targeting tumor stroma and exploiting mature tumor vasculature to improve anti-cancer drug delivery. Drug Resist Updat 10: 109–120.

    Article  CAS  PubMed  Google Scholar 

  • Bruchovsky N . (1993) In: Holland JF, Frei E III, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum RR, (eds). Androgens and antiandrogens. Cancer Medicine, 3rd ed Lea & Febiger: Philadelphia, pp 884–896.

    Google Scholar 

  • Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, To M, Lawson D . (1990). Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 50: 2275–2282.

    CAS  PubMed  Google Scholar 

  • Bruchovsky N, Wilson JD . (1968). The conversion of testosterone to 5-alpha-androstan-17-beta-ol-3-one by rat prostate in vivo and in vitro. J Biol Chem 243: 2012–2021.

    Article  CAS  PubMed  Google Scholar 

  • Buchanan G, Irvine RA, Coetzee GA, Tilley WD . (2001). Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev 20: 207–223.

    Article  CAS  PubMed  Google Scholar 

  • Chodak GW, Kranc DM, Puy LA, Takeda H, Johnson K, Chang C . (1992). Nuclear localization of androgen receptor in heterogeneous samples of normal, hypeplastic and neoplastic human prostate. J Urol 147: 798–803.

    Article  CAS  PubMed  Google Scholar 

  • Condon MS . (2005). The role of the stromal microenviroment in prostate cancer. Semin Cancer Biol 15: 132–137.

    Article  PubMed  Google Scholar 

  • Crook JM, Szumacher E, Malone S, Huan S, Segal R . (1999). Intermittent androgen suppression in the management of prostate cancer. Urology 53: 530–534.

    Article  CAS  PubMed  Google Scholar 

  • Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ et al. (1987). The endocrinology and developmental biology of the prostate. Endocr Rev 8: 338–362.

    Article  CAS  PubMed  Google Scholar 

  • Cunha GR, Hayward SW, Wang YZ, Ricke WA . (2003). Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer 107: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Chuu C-P, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S . (2006). Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist. Cancer Res 66: 6482–6486.

    Article  CAS  PubMed  Google Scholar 

  • Denis LJ, Griffiths K . (2000). Endocrine treatment in prostate cancer Sem. Surg Oncol 18: 52–74.

    Article  CAS  Google Scholar 

  • Eder IE, Culig Z, Ramoner R, Thurnher M, Putz T, Nessler-Menardi C et al. (2000). Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides. Cancer Gene Ther 7: 997–1007.

    Article  CAS  PubMed  Google Scholar 

  • Eder IE, Hoffmann J, Rogatsch H, Schäfer G, Zopf D, Bartsch G et al. (2002). Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor. Cancer Gene Ther 9: 117–125.

    Article  CAS  PubMed  Google Scholar 

  • Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ et al. (1998). Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036–1042.

    Article  CAS  PubMed  Google Scholar 

  • Ferreira U, Leitao VA, Denardi F, Matheus WE, Stopiglia RM, Netto Jr NR . (2006). Intermittent androgen replacement for intense hypogonadism symptoms in castrated patients. Prostate Cancer Prostatic Dis 9: 39–41.

    Article  CAS  PubMed  Google Scholar 

  • Fowler JE, Whimore WF . (1981). The response to metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 126: 372–375.

    Article  PubMed  Google Scholar 

  • Garcia-Arenas R, Lin FF, Lin D, Jin LP, Shih CC, Chang C et al. (1995). The expression of prostatic acid phosphotase is transcriptionally regulated in human prostate carcinoma cells. Mol Cell Endocrinol 111: 29–37.

    Article  CAS  PubMed  Google Scholar 

  • George DJ, Dionne CA, Jani J, Angeles T, Murakata C, Lamb J et al. (1999). Sustained in vivo regression of Dunning H rat prostate cancers treated with combination of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res 59: 2395–2401.

    CAS  PubMed  Google Scholar 

  • Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM . (1991). Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res 57: 4687–4691.

    Google Scholar 

  • Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LW . (1991). Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res 51: 3753–3761.

    CAS  PubMed  Google Scholar 

  • Hååg P, Bektic J, Bartsch G, Klocker H, Eder IE . (2005). Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as androgen independent prostate cancer cells. J Steroid Biochem Mol Biol 96: 251–258.

    Article  PubMed  CAS  Google Scholar 

  • Halin S, Hammarsten P, Wikström P, Bergh A . (2007). Androgen-independent prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment. Prostate 67: 370–377.

    Article  PubMed  Google Scholar 

  • Heinlein CA, Chang C . (2002). Androgen receptor (AR) coregulators: an overview. Endocr Rev 23: 175–200.

    Article  CAS  PubMed  Google Scholar 

  • Heinlein CA, Chang C . (2004). Androgen receptor in prostate cancer. Endocr Rev 25: 276–308.

    Article  CAS  PubMed  Google Scholar 

  • Heisler LE, Evangelou A, Lew AM, Trachtenberg J, Elsholtz HP, Brown TJ . (1997). Androgen independent cell cycle arrest and apoptotic death in PC-3 prostatic cell cultures expressing a full-length human androgen receptor. Mol Cell Endocrinol 126: 59–73.

    Article  CAS  PubMed  Google Scholar 

  • Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A . (1996). Androgen receptor status of lymph node metastases from prostate cancer. Prostate 28: 129–135.

    Article  CAS  PubMed  Google Scholar 

  • Hofmeister V, Schrama D, Becker JC . (2008). Anti-cancer therapies targeting the tumor stroma. Cancer Immunol Immunother 57: 1–17.

    Article  CAS  PubMed  Google Scholar 

  • Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM et al. (1983). LNCaP model of human prostatic carcinoma. Cancer Res 43: 1809–1818.

    CAS  PubMed  Google Scholar 

  • Huggins C, Hodges CV . (1941). Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293–297.

    CAS  Google Scholar 

  • Hurtado-Coll A, Goldenberg SL, Gleave ME, Klotz L . (2002). Intermittent androgen suppression in prostate cancer: the Canadian experience. Urology 60 (3 Suppl 1): 52–56.

    Article  PubMed  Google Scholar 

  • Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF . (2002). Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 50: 222–235.

    Article  CAS  PubMed  Google Scholar 

  • Inui S, Fukuzato Y, Nakajima T, Yoshikawa K, Itami S . (2002). Androgen-inducible TGF-β1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth. FASEB J 16: 1967–1969.

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Ward E, Hao Y, Thun M . (2005). Trends in the leading cause of death in the United States. JAMA 294: 1255–1259.

    Article  CAS  PubMed  Google Scholar 

  • Johansson A, Jones J, Pietras K, Kiltler S, Skytt A, Rudolfsson SH et al. (2007). A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model. Prostate 67: 1664–1676.

    Article  CAS  PubMed  Google Scholar 

  • Johnson MA, Iversen P, Schwier P, Corn AL, Sandusky G, Graff J et al. (2005). Castration triggers growth of previously static androgen-independent lesions in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Prostate 62: 322–338.

    Article  PubMed  Google Scholar 

  • Joly-Pharaboz MO, Ruffion A, Roch A, Michel-Calemard L, André J, Chantepie J et al. (2000). Inhibition of growth and induction of apoptosis by androgens of a variant of LNCaP cell line. J Steroid Biochem Mol Biol 73: 237–249.

    Article  CAS  PubMed  Google Scholar 

  • Kaighn ME, Narayan KS, Ohnuki Y, Lechner JF, Jones LW . (1979). Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest Urol 17: 16–23.

    CAS  PubMed  Google Scholar 

  • Kaufman JM, Graydon J . (2004). Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 172: 920–922.

    Article  CAS  PubMed  Google Scholar 

  • Khera M, Grober ED, Naiari B, Colen JS, Mohamed O, Lamb DJ et al. (2009). Testosterone replacement therapy following radical prostatectomy. J Sex Med 6: 1165–1170.

    Article  CAS  PubMed  Google Scholar 

  • Kleeberger W, Bova GS, Nielsen ME, Herawi M, Chuang AY, Epstein JI et al. (2007). Roles of the stem cell-associated intermediate filament nestin in prostate cancer migration and metastasis. Cancer Res 67: 9199–9206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kokontis JM, Hay S, Liao S . (1998). 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 12: 941–953.

    Article  CAS  PubMed  Google Scholar 

  • Kokontis JM, Takakura K, Hay N, Liao S . (1994). Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res 54: 1566–1573.

    CAS  PubMed  Google Scholar 

  • Kühn R, Schwenk F, Aguet M, Rajewsky K . (1995). Inducible gene targeting in mice. Science 269: 1427–1429.

    Article  PubMed  Google Scholar 

  • Liao X, Tang S, Thrasher JB, Griebling TL, Li B . (2005). Small interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol Cancer Ther 4: 505–515.

    Article  CAS  PubMed  Google Scholar 

  • Litvinov IV, Antony L, Dalrymple SL, Becker R, Cheng L, Isaacs JT . (2006). PC-3, but not DU145, human prostate cancer cells retain the coregulators required for tumor suppressor ability of androgen receptor. Prostate 66: 1329–1338.

    Article  CAS  PubMed  Google Scholar 

  • Litvinov IV, Antony L, Isaacs JT . (2004). Molecular characterization of an improved vector for evaluation of the tumor suppressor versus oncogene abilities of the androgen receptor. Prostate 61: 299–304.

    Article  CAS  PubMed  Google Scholar 

  • Litvinov IV, De Marzo AM, Isaacs JT . (2003). Is the Achilles’ heel for prostate cancer therapy: a gain of function in androgen receptor signaling? J Clin Endocrinol Metab 88: 2972–2982.

    Article  CAS  PubMed  Google Scholar 

  • Liu AY, Roudier MP, True LD . (2004). Heterogeneity in primary and metastatic prostate cancer as defined by cell surface CD profile. Am J Pathol 165: 1543–1556.

    Article  PubMed  PubMed Central  Google Scholar 

  • Marques RB, Erkens-Schulze S, de Ridder CM, Hermans KG, Waltering K, Visakorpi T et al. (2005). Androgen receptor modifications in prostate cancer cells upon long-term androgen ablation and antiandrogen treatment. Int J Cancer 117: 221–229.

    Article  CAS  PubMed  Google Scholar 

  • Mathew P . (2008). Prolonged control of progressive castration-resistant metastatic prostate cancer with testosterone replacement therapy: the case of a prospective trial. Ann Oncol 19: 395–403.

    Article  CAS  PubMed  Google Scholar 

  • Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG et al. (2001). T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci USA 98: 14565–14570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mirosevich J, Bentel JM, Zeps N, Redmond SL, D'Antuono MF, Dawkins HJ . (1999). Androgen receptor expression in proliferating basal and luminal cells in adult murine ventral prostate. J Endocrinol 162: 341–350.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto H, Altuwaijri S, Cai Y, Messing EM, Chang C . (2005). Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer. Mol Carcinog 44: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Mohler JL, Chen Y, Hamil K, Hall SH, Sidlowski JA, Wilson EM et al. (1996). Androgen and glucocorticoid receptors in the stroma and epithelium of prostatic hyperplasia and carcinoma. Clin Cancer Res 2: 889–895.

    CAS  PubMed  Google Scholar 

  • Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C et al. (2009). Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Eur Urol 56: 237–244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD et al. (2007). Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration resistant prostate cancer. Cancer Res 67: 5033–5041.

    Article  CAS  PubMed  Google Scholar 

  • Nagabhushan M, Miller CM, Pretlow TP, Giaconia JM, Edgehouse NL, Schwartz S et al. (1996). CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Cancer Res 56: 3042–3046.

    CAS  PubMed  Google Scholar 

  • Nelius T, Filleur S, Yemelyanov A, Budunova I, Shroff E, Mirochnik Y et al. (2007). Androgen receptor target NFkB and TSP1 to suppress prostate tumor growth in vivo. Int J Cancer 121: 999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM et al. Androgen receptor is a tumor suppressor and stimulator in prostate cancer. Proc Natl Acad Sci USA, (2008a) 105: 12182–12187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niu Y, Altuwaijri S, Yeh S, Lai KP, Yu S, Chuang KH et al. (2008b). Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc Natl Acad Sci USA 105: 12188–12193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olea N, Sakabe K, Soto AM, Sonnenschein C . (1990). The proliferative effect of ‘anti-androgens’ on the androgen-sensitive human prostate tumor cell line LNCaP. Encocrinology 126: 1457–1463.

    Article  CAS  Google Scholar 

  • Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR . (1999). Carcinoma-associated fibroblasts direct tumor progression in initiated human prostatic epithelium. Cancer Res 59: 5002–5011.

    CAS  PubMed  Google Scholar 

  • Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S et al. (2006). Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25: 1696–1708.

    Article  CAS  PubMed  Google Scholar 

  • Pinkas J, Teicher BA . (2006). TGF-β in cancer and as a therapeutic target. Biochem Pharmacol 72: 523–529.

    Article  CAS  PubMed  Google Scholar 

  • Rahman M, Miyamoto H, Chang C . (2004). Androgen receptor coregulators in prostate cancer: mechanism and clinical implication. Clin Cancer Res 10: 2208–2219.

    Article  CAS  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

    Article  CAS  PubMed  Google Scholar 

  • Ricke WA, Ishii K, Ricke EA, Simko J, Wang Y, Hayward SW et al. (2006). Steroid hormones stimulate human prostate cancer progression and metastasis. Int J Cancer 118: 123–2131.

    Article  CAS  Google Scholar 

  • Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK et al. (1999). Regulation of androgen action. Vit Horm 55: 309–352.

    Article  CAS  Google Scholar 

  • Sadi MV, Walsh PC, Barrack ER . (1991). Immunohistochemical study of androgen receptors in metastatic prostate cancer. Cancer 67: 3057–3064.

    Article  CAS  PubMed  Google Scholar 

  • Schmitt B, Wilt TJ, Schellhammer PF, DeMasi V, Sartor O, Crawford ED et al. (2001). Combined androgen blockade with non-steroidal anti-androgens for advanced prostate cancer. A systemic review. Urology 57: 727–732.

    Article  CAS  PubMed  Google Scholar 

  • Shimazaki J, Kurihara H, Ito Y, Shida K . (1965). Testosterone metabolism in prostate; formation of androstan-17-beta-ol-3-one and androst-4-ene-3, 17-dione, and inhibitory effect of natural and synthetic estrogens. Gunma J Med Sci 14: 313–325.

    CAS  PubMed  Google Scholar 

  • Soto AM, Lin TM, Sakabe K, Olea N, Damassa DA, Sonnenschein C . (1995). Variants of the human prostate LNCaP cell line as tools to study discrete components of the androgen-mediated proliferative response. Oncol Res 7: 545–558.

    CAS  PubMed  Google Scholar 

  • Szmulewitz R, Mohile S, Posadas E, Kunnayakkam R, Karrison T, Manchen E et al. (2009). A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer. Eur Urol 56: 97–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor LG, Canfield SE, Du X . (2009). Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 115: 2388–2399.

    Article  PubMed  Google Scholar 

  • Thompson TC, Timme TL, Kadmon D, Park SH, Egawa S, Yoshida K . (1993). Genetic predisposition and mesenchymal-epithelial interactions in ras myc-induced carcinogenesis I reconstituted mouse prostate. Mol Carcinog 7: 165–179.

    Article  CAS  PubMed  Google Scholar 

  • Tokar EJ, Ancrile BB, Cunha GR, Webber MM . (2005). Stem/progenitor and intermediate cell types and the origin of human prostate cancer. Differentiation 73: 463–473.

    Article  CAS  PubMed  Google Scholar 

  • van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL et al. (2003). Molecular characterization of human prostate carcinoma cell lines. Prostate 57: 205–225.

    Article  CAS  PubMed  Google Scholar 

  • van der Kwast TH, Schalken J, Ruizeveld de Winter JA, van Vroonhoven CC, Mulder E, Boersma W et al. (1991). Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 48: 189–193.

    Article  CAS  PubMed  Google Scholar 

  • van Leender GJ, Aalders TW, Hulsbergen-van de Kaa CA, Ruiter DJ, Schalken JA . (2001). Expression of basal cell keratins in human prostate cancer metastases and cell lines. J Pathol 195: 563–570.

    Article  Google Scholar 

  • van Leenders GJLH, Schalken JA . (2003). Epithelial cell differentiation in the human prostate epithelium: implications for the pathogenesis and therapy of prostate cancer. Oncol Hemat 46: S3–S10.

    Google Scholar 

  • Thalmann GN, Sikes RA, Wu TT, Degeorges A, Chang SM, Ozen M et al. (2000). LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate 44: 91–103.

    Article  CAS  PubMed  Google Scholar 

  • Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL . (2005). Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 11: 4653–4657.

    Article  CAS  PubMed  Google Scholar 

  • van Weerden WM, de Ridder CM, Verdaasdonk CL, Romijn JC, van der Kwast TH, Schröder FH et al. (1996). Development of seven new human prostate tumor xenograft models and their histopathological characterization. Am J Pathol 149: 1055–1062.

    CAS  PubMed  PubMed Central  Google Scholar 

  • van Weerden WM, Romijn JC . (2000). Use of nude mouse xenograft models in prostate cancer research. Prostate 43: 263–271.

    Article  CAS  PubMed  Google Scholar 

  • Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E et al. (1990). A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androtens. Biochem Biophys Res Commun 17: 534–540.

    Article  Google Scholar 

  • Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C et al. (2005). in vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9: 401–406.

    Article  Google Scholar 

  • Wainstein MA, He F, Robinson D, Kung HJ, Schwartz S, Giaconia JM et al. (1994). CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res 54: 6049–6052.

    CAS  PubMed  Google Scholar 

  • Wang L, Hsu C-L, Chang C . (2005). Androgen receptor corepressors: an overview. Prostate 63: 117–130.

    Article  CAS  PubMed  Google Scholar 

  • Wang XD, Leow CC, Zha J, Tang Z, Modrusan Z, Radtke F et al. (2006). Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Dev Biol 290: 66–80.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Sudilovsky D, Zhang B, Haughney PC, Rosen MA, Wu DS et al. (2001). A human prostatic epithelial model of hormonal cacinogenesis. Cancer Res 61: 6064–6072.

    CAS  PubMed  Google Scholar 

  • Webber MM, Trakul N, Thraves PS, Bello-DeOcampo D, Chu WW, Storto PD et al. (1999). A human prostatic stromal myofibroblast cell line WPMY-1: a model for stromal-epithelial interactions in prostatic neoplasia. Carcinogenesis 20: 1185–1192.

    Article  CAS  PubMed  Google Scholar 

  • Wu CT, Altuwaijri S, Ricke WA, Huang SP, Yeh S, Zhang C et al. (2007). Increased prostate cell proliferation and loss of cell differentiation in mice lacking epithelial androgen receptor. Proc Natl Acad Sci USA 104: 12679–12684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Chang YJ, Yu IC, Miyamoto H, Wu CC, Yeh S et al. (2007). ASC-J9 ameliorates spinal and bulbar muscular atrophyphenotype via degradation of androgen receptor. Nature Medicine 13: 348–353.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J-R, Yu L, Zerbini LF, Libermann TA, Blackburn GL . (2004). Progression to androgen-independent LNCaP human prostate tumors: cellular and molecular alterations. Int J Cancer 110: 800–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the George Whipple Professorship and NIH grant CA122840 and NSFC grant project 30872587.

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Author notes

  1. Y Niu and T-M Chang: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pathology, Urology, Radiation Oncology and Wilmot Cancer Center, George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY, USA

    Y Niu, T-M Chang, S Yeh, W-L Ma & C Chang

  2. Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, China

    Y Niu

  3. Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan, ROC

    W-L Ma

  4. Department of Urological Sciences, University of British Columbia, Vancouver, Canada

    Y Z Wang

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ASC-J9 was patented by the University of Rochester, the University of North Carolina, and AndroScience Corp., and then licensed to AndroScience Corp. Both the University of Rochester and C Chang own royalties and equity in AndroScience Corp.

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Niu, Y., Chang, TM., Yeh, S. et al. Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails. Oncogene 29, 3593–3604 (2010). https://doi.org/10.1038/onc.2010.121

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  • DOI: https://doi.org/10.1038/onc.2010.121

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