Role of dutasteride in pre‐clinical ETS fusion‐positive prostate cancer models
dc.contributor.author | Ateeq, Bushra | en_US |
dc.contributor.author | Vellaichamy, Adaikkalam | en_US |
dc.contributor.author | Tomlins, Scott A. | en_US |
dc.contributor.author | Wang, Rui | en_US |
dc.contributor.author | Cao, Qi | en_US |
dc.contributor.author | Lonigro, Robert J. | en_US |
dc.contributor.author | Pienta, Kenneth J. | en_US |
dc.contributor.author | Varambally, Sooryanarayana | en_US |
dc.date.accessioned | 2012-09-05T14:46:15Z | |
dc.date.available | 2013-11-15T16:44:23Z | en_US |
dc.date.issued | 2012-10-01 | en_US |
dc.identifier.citation | Ateeq, Bushra; Vellaichamy, Adaikkalam; Tomlins, Scott A.; Wang, Rui; Cao, Qi; Lonigro, Robert J.; Pienta, Kenneth J.; Varambally, Sooryanarayana (2012). "Role of dutasteride in pre‐clinical ETS fusion‐positive prostate cancer models." The Prostate 72(14): 1542-1549. <http://hdl.handle.net/2027.42/93574> | en_US |
dc.identifier.issn | 0270-4137 | en_US |
dc.identifier.issn | 1097-0045 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/93574 | |
dc.description.abstract | BACKGROUND Androgens play a crucial role in prostate cancer, hence the androgenic pathway has become an important target of therapeutic intervention. Previously we discovered that gene fusions between the 5′‐untranslated region of androgen regulated gene TMPRSS2 and the ETS transcription factor family members were present in a majority of the prostate cancer cases. The resulting aberrant overexpression of ETS genes drives tumor progression. METHODS Here, we evaluated the expression levels of 5α‐reductase isoenzymes in prostate cancer cell lines and tissues. We tested the effect of dutasteride, a 5α‐reductase inhibitor, in TMPRSS2–ERG fusion‐positive VCaP cell proliferation and cell invasion. We also evaluated the effect of dutasteride on the TMPRSS2–ERG fusion gene expression. Finally, we tested dutasteride alone or in combination with an anti‐androgen in VCaP cell xenografts tumor model. RESULTS Our data showed that 5α‐reductase SRD5A1 and SRD5A3 isoenzymes that are responsible for the conversion of testosterone to DHT, are highly expressed in metastatic prostate cancer compared to benign and localized prostate cancer. Dutasteride treatment attenuated VCaP cell proliferation and invasion. VCaP cells pre‐treated with dutasteride showed a reduction in ERG and PSA expression. In vivo studies demonstrated that dutasteride in combination with the anti‐androgen bicalutamide significantly decreased tumor burden in VCaP cell xenograft model. CONCLUSIONS Our findings suggest that dutasteride can inhibit ERG fusion‐positive cell growth and in combination with anti‐androgen, significantly reduce the tumor burden. Our study suggests that anti‐androgens used in combination with dutasteride could synergistically augment the therapeutic efficacy in the treatment of ETS‐positive prostate cancer. Prostate 72:1542–1549, 2012. © 2012 Wiley Periodicals, Inc. | en_US |
dc.publisher | Wiley Subscription Services, Inc., A Wiley Company | en_US |
dc.subject.other | Gene Fusion | en_US |
dc.subject.other | 5α‐Reductase | en_US |
dc.subject.other | TMPRSS2–ERG | en_US |
dc.subject.other | Prostate Cancer | en_US |
dc.subject.other | Dutasteride | en_US |
dc.title | Role of dutasteride in pre‐clinical ETS fusion‐positive prostate cancer models | en_US |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | en_US |
dc.subject.hlbsecondlevel | Internal Medicine and Specialties | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.peerreviewed | Peer Reviewed | en_US |
dc.contributor.affiliationum | Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan | en_US |
dc.contributor.affiliationum | Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan | en_US |
dc.contributor.affiliationum | Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan | en_US |
dc.contributor.affiliationum | Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan | en_US |
dc.contributor.affiliationum | Department of Pathology, University of Michigan Medical School, Traverwood IV, Suite 100, 2900 Huron Parkway, Ann Arbor, MI 48109‐0602. | en_US |
dc.contributor.affiliationother | Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX 77030. | en_US |
dc.identifier.pmid | 22415461 | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/93574/1/22509_ftp.pdf | |
dc.identifier.doi | 10.1002/pros.22509 | en_US |
dc.identifier.source | The Prostate | en_US |
dc.identifier.citedreference | Barqawi AB, O'Donnell CI, Siomos VJ, Hou AH. The effect of short‐term dutasteride intake in early‐stage prostate cancer: Analysis of 148 patients who underwent three‐dimensional prostate mapping biopsy. Urology 2010; 76 ( 5 ): 1067 – 1071;. | en_US |
dc.identifier.citedreference | Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, Cao X, Wei JT, Rubin MA, Shah RB, Chinnaiyan AM. TMPRS S2: ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res 2006; 66 ( 7 ): 3396 – 3400;. | en_US |
dc.identifier.citedreference | Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 2003; 100 ( 20 ): 11606 – 11611;. | en_US |
dc.identifier.citedreference | Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B, Shaheduzzaman S, Tan SH, Vaidyanathan G, Whitman E, Hawksworth DJ, Chen Y, Nau M, Patel V, Vahey M, Gutkind JS, Sreenath T, Petrovics G, Sesterhenn IA, McLeod DG, Srivastava S. TMPRSS2–ERG fusion, a common genomic alteration in prostate cancer activates C‐MYC and abrogates prostate epithelial differentiation. Oncogene 2008; 27 ( 40 ): 5348 – 5353;. | en_US |
dc.identifier.citedreference | Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310 ( 5748 ): 644 – 648;. | en_US |
dc.identifier.citedreference | Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q, Han B, Yu J, Wang L, Montie JE, Rubin MA, Pienta KJ, Roulston D, Shah RB, Varambally S, Mehra R, Chinnaiyan AM. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 2007; 448 ( 7153 ): 595 – 599;. | en_US |
dc.identifier.citedreference | Kumar‐Sinha C, Tomlins SA, Chinnaiyan AM. Recurrent gene fusions in prostate cancer. Nat Rev 2008; 8 ( 7 ): 497 – 511;. | en_US |
dc.identifier.citedreference | Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB, Mehra R, Chinnaiyan AM. Role of the TMPRSS2–ERG gene fusion in prostate cancer. Neoplasia 2008; 10 ( 2 ): 177 – 188;. | en_US |
dc.identifier.citedreference | Mostaghel EA, Geng L, Holcomb I, Coleman IM, Lucas J, True LD, Nelson PS. Variability in the androgen response of prostate epithelium to 5alpha‐reductase inhibition: Implications for prostate cancer chemoprevention. Cancer Res 2010; 70 ( 4 ): 1286 – 1295;. | en_US |
dc.identifier.citedreference | Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, Black L, Rittmaster RS. Dutasteride in localised prostate cancer management: The REDEEM randomised, double‐blind, placebo‐controlled trial. Lancet 2012; [Epub ahead of print]. | en_US |
dc.identifier.citedreference | Olsson Gisleskog P, Hermann D, Hammarlund‐Udenaes M, Karlsson MO. Validation of a population pharmacokinetic/pharmacodynamic model for 5alpha‐reductase inhibitors. Eur J Pharm Sci 1999; 8 ( 4 ): 291 – 299;. | en_US |
dc.identifier.citedreference | Chang KH, Li R, Papari‐Zareei M, Watumull L, Zhao YD, Auchus RJ, Sharifi N. Dihydrotestosterone synthesis bypasses testosterone to drive castration‐resistant prostate cancer. Proc Natl Acad Sci USA 2011; 108 ( 33 ): 13728 – 13733;. | en_US |
dc.identifier.citedreference | Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, Nakagawa H. Novel 5alpha‐steroid reductase (SRD5A3, type‐3) is overexpressed in hormone‐refractory prostate cancer. Cancer Sci 2008; 99 ( 1 ): 81 – 86;. | en_US |
dc.identifier.citedreference | Tindall DJ, Rittmaster RS. The rationale for inhibiting 5alpha‐reductase isoenzymes in the prevention and treatment of prostate cancer. J Urol 2008; 179 ( 4 ): 1235 – 1242;. | en_US |
dc.identifier.citedreference | Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5alpha‐reductase inhibition in human benign prostatic hyperplasia. World J Urol 2002; 19 ( 6 ): 413 – 425;. | en_US |
dc.identifier.citedreference | Nacusi LP, Tindall DJ. Targeting 5alpha‐reductase for prostate cancer prevention and treatment. Nat Rev Urol 2011; 8 ( 7 ): 378 – 384;. | en_US |
dc.identifier.citedreference | Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: Further evidence for frequent continued hormone‐dependence in castration‐resistant prostate cancer. Br J Cancer 2009; 100 ( 5 ): 671 – 675;. | en_US |
dc.identifier.citedreference | Gillatt D. Antiandrogen treatments in locally advanced prostate cancer: Are they all the same ? J Cancer Res Clin Oncol 2006; 132 ( Suppl 1 ): S17 – S26;. | en_US |
dc.identifier.citedreference | Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM. An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 2010; 17 ( 5 ): 443 – 454;. | en_US |
dc.identifier.citedreference | King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, Taylor BS, Sander C, Cardiff RD, Couto SS, Gerald WL, Sawyers CL. Cooperativity of TMPRSS2–ERG with PI3‐kinase pathway activation in prostate oncogenesis. Nat Genet 2009; 41 ( 5 ): 524 – 526;. | en_US |
dc.identifier.citedreference | Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, Nelson PS, Vasioukhin V. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci USA 2008; 105 ( 6 ): 2105 – 2110;. | en_US |
dc.identifier.citedreference | Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith‐Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second‐generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324 ( 5928 ): 787 – 790;. | en_US |
dc.identifier.citedreference | Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration‐resistant prostate cancer. Clin Cancer Res 2009; 15 ( 22 ): 7099 – 7105;. | en_US |
dc.identifier.citedreference | Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS. Effect of dutasteride on the risk of prostate cancer. New Engl J Med 2010; 362 ( 13 ): 1192 – 1202;. | en_US |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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