Androgen Regulation of Prostate Cancer Gene Fusions

  • Rou Wang
  • Scott A. Tomlins
  • Arul M. Chinnaiyan


Recurrent chromosomal rearrangements were not well characterized in epithelial malignancies until the recent discovery of recurrent fusions of TMPRSS2 and ETS transcription factors in prostate cancer. Since the initial discovery of the TMPRSS2:ETS gene fusions, multiple other 5′ and 3′ fusion partners have been discovered, which led to the identification of five different classes of ETS gene rearrangements to date. These rearrangements demonstrate variable response to androgen stimulation, and ultimately, may help tailor androgen-deprivation therapy for patients with advanced prostate cancer. Initial studies have demonstrated that ETV1 overexpression mediates invasion in prostate cell lines, though secondary factors may be required for the development of frank malignancy. TMPRSS2:ETS gene fusions may confer a more aggressive phenotype, and fusion status has been linked to adverse clinical factors, such as higher tumor stage and nodal metastases. ETS factor fusions are likely an important contributor to human prostate cancer development and progression, though more research will be needed to elucidate their regulation by androgen and clinical functionality. Ultimately, identification of distinct gene fusion status may allow for risk stratification and tailored treatment of patients with prostate cancer.


Prostate Cancer Androgen Receptor Gene Fusion Abiraterone Acetate Seminal Vesicle Invasion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Afar, D.E., Vivanco, I., Hubert, R.S., et al. 2001. Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia. Cancer Research 61:1686–1692.PubMedGoogle Scholar
  2. Attard, G., Belldegrun, A.S., and de Bono, J.S. 2005. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU International 96:1241–1246.PubMedCrossRefGoogle Scholar
  3. Barry, M., Perner, S., Demichelis, F., et al. 2007. TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70:630–633.PubMedCrossRefGoogle Scholar
  4. Cerveira, N., Ribeiro, F.R., Peixoto, A., et al. 2006. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8:826–832.PubMedCrossRefGoogle Scholar
  5. Chen, C.D., Welsbie, D.S., Tran, C., et al. 2004. Molecular determinants of resistance to antiandrogen therapy. Nature Medicine10:33–39.PubMedCrossRefGoogle Scholar
  6. Dhanasekaran, S.M., Barrette, T.R., Ghosh, D., et al. 2001. Delineation of prognostic biomarkers in prostate cancer. Nature 412:822–826.PubMedCrossRefGoogle Scholar
  7. Dhanasekaran, S.M., Dash, A., Yu, J., et al. 2005. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEB Journal 19:243–245.PubMedGoogle Scholar
  8. Deininger, M., Buchdunger, E., and Druker, B.J. 2005. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653.PubMedCrossRefGoogle Scholar
  9. de Klein, A., van Kessel, A.G., Grosveld, G., et al. 1982. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300:765–767.PubMedCrossRefGoogle Scholar
  10. Demichelis, F., Fall, K., Perner, S., et al. 2007. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26:4596–4599.PubMedCrossRefGoogle Scholar
  11. Gleason, D.F., and Mellinger, G.T. 1974. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. Journal of Urology 111:58–64.PubMedGoogle Scholar
  12. Glinsky, G.V., Glinskii, A.B., Stephenson, A.J., et al. 2004. Gene expression profiling predicts clinical outcome of prostate cancer. The journal of Clinical Investigation 113:913–923.PubMedGoogle Scholar
  13. Helgeson, B.E., Tomlins, S.A., Shah, N., et al. 2008. Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Research 68:73–80.PubMedCrossRefGoogle Scholar
  14. Hendriksen, P.J., Dits, N.F., Kokame, K., et al. 2006. Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Research 66:5012–5020.Google Scholar
  15. Hermans, K.G., van Marion, R., van Dekken, H., et al. 2006. TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Research 66:10658–10663.PubMedCrossRefGoogle Scholar
  16. Hessels, D., Smit, F.P., Verhaegh, G.W., et al. 2007. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clinical Cancer Research 13:5103–5108.PubMedCrossRefGoogle Scholar
  17. Hsu, T., Trojanowska, M., and Watson, D.K. 2004. Ets proteins in biological control and cancer. Journal of Cellular Biochemistry 91:896–903.PubMedCrossRefGoogle Scholar
  18. Huang, Y.Q., Li, J.J., Hu, L., et al. 2001. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes. Thrombosis & Haemostasis 86:1094–1098.Google Scholar
  19. Huggins, C., and Hodges, C.V. 2002. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. Journal of Urology 168:9–12.PubMedCrossRefGoogle Scholar
  20. Jacquinet, E., Rao, N.V., Rao, G.V., et al. 2001. Cloning and characterization of the cDNA and gene for human epitheliasin. European Journal of Biochemistry 268:2687–2699.PubMedCrossRefGoogle Scholar
  21. Jemal, A., Siegel, R., Ward, E., et al. 2008. Cancer statistics, 2008. CA: a Cancer Journal for Clinicians 58:71–96.CrossRefGoogle Scholar
  22. Kasper, S., Cookson, M.S. 2006. Mechanisms leading to the development of hormone-resistant prostate cancer. Urologic Clinics of North America 33:201–210.PubMedCrossRefGoogle Scholar
  23. Kaushal, V., Kohli, M., Dennis, R.A., et al. 2006. Thrombin receptor expression is upregulated in prostate cancer. Prostate 66:273–282.PubMedCrossRefGoogle Scholar
  24. Lapointe, J., Li, C., Higgins, J.P., et al. 2004. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 101:811–816.PubMedCrossRefGoogle Scholar
  25. Lapointe, J., Kim, Y.H., Miller, M.A., et al. 2007. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Modern Pathology 20:467–473.PubMedCrossRefGoogle Scholar
  26. Laxman, B., Tomlins, S.A., Mehra, R., et al. 2006. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia 8:885–888.PubMedCrossRefGoogle Scholar
  27. Laxman, B., Morris, D.S., Yu, J., et al. 2008. A first generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Research 68:645–649.PubMedCrossRefGoogle Scholar
  28. Lin, B., Ferguson, C., White, J.T., et al. 1999. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Research 59:4180–4184.PubMedGoogle Scholar
  29. Liu, A.Y., Brubaker, K.D., Goo, Y.A., et al. 2004. Lineage relationship between LNCaP and LNCaP-derived prostate cancer cell lines. Prostate 60:98–108.PubMedCrossRefGoogle Scholar
  30. Marcucci, G., Baldus, C.D., Ruppert, A.S., et al. 2005. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. Journal of Clinical Oncology 23:9234–9242.PubMedCrossRefGoogle Scholar
  31. Mehra, R., Han, B., Tomlins, S.A., et al. 2007a. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Research 67:7991–7995.CrossRefGoogle Scholar
  32. Mehra, R., Tomlins, S.A., Shen, R., et al. 2007b. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Modern Pathology 20:538–544.CrossRefGoogle Scholar
  33. Mertz, K.D., Setlur, S.R., Dhanasekaran, S.M., et al. 2007. Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9:200–206.PubMedCrossRefGoogle Scholar
  34. Mitelman, F., Johansson, B., and Mertens, F. 2007. The impact of translocations and gene fusions on cancer causation. Nature Reviews Cancer 7:233–245.PubMedCrossRefGoogle Scholar
  35. Mosquera, J.M., Perner, S., Demichelis, F., et al. 2007. Morphological features of TMPRSS2-ERG gene fusion prostate cancer. Journal of Pathology 212:91–101.PubMedCrossRefGoogle Scholar
  36. Murillo, H., Schmidt, L.J., Karter, M., et al. 2006. Prostate cancer cells use genetic and epigenetic mechanisms for progression to androgen independence. Genes, Chromosomes & Cancer 45:702–716.CrossRefGoogle Scholar
  37. Nam, R.K., Sugar, L., Yang, W., et al. 2007. Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. The British Journal of Cancer 97:1690–1695.CrossRefGoogle Scholar
  38. O'Donnell, A., Judson, I., Dowsett, M., et al. 2004. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. British Journal of Cancer 90:2317–2325.PubMedGoogle Scholar
  39. Oikawa, T., and Yamada, T. 2003. Molecular biology of the Ets family of transcription factors. Gene 303:11–34.PubMedCrossRefGoogle Scholar
  40. Oudes, A.J., Roach, J.C., Walashek, L.S., et al. 2005. Application of Affymetrix array and Massively Parallel Signature Sequencing for identification of genes involved in prostate cancer progression. BMC Cancer 5:86.PubMedCrossRefGoogle Scholar
  41. Paoloni-Giacobino, A., Chen, H., Peitsch, M.C., et al. 1997. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics 44:309–320.PubMedCrossRefGoogle Scholar
  42. Perner, S., Demichelis, F., Beroukhim, R., et al. 2006. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Research 66:8337–8341.PubMedCrossRefGoogle Scholar
  43. Perner, S., Mosquera, J.M., Demichelis, F., et al. 2007. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. American Journal of Surgical Pathology 31:882–888.PubMedCrossRefGoogle Scholar
  44. Rabbitts, T.H. 1994. Chromosomal translocations in human cancer. Nature 372:143–149.PubMedCrossRefGoogle Scholar
  45. Rhodes, D.R., Kalyana-Sundaram, S., Mahavisno, V., et al. 2007. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9:166–180.PubMedCrossRefGoogle Scholar
  46. Rowley, J.D. 1973. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–293.PubMedCrossRefGoogle Scholar
  47. Salah, Z., Maoz, M., Cohen, I., et al. 2005. Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression. FASEB Journal 19:62–72.PubMedCrossRefGoogle Scholar
  48. Shi, X.B., Ma, A.H., Tepper, C.G., et al. 2004a. Molecular alterations associated with LNCaP cell progression to androgen independence. Prostate 60:257–271.CrossRefGoogle Scholar
  49. Shi, X., Gangadharan, B., Brass, L.F., et al. 2004b. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Molecular Cancer Research 2:395–402.Google Scholar
  50. Soller, M.J., Isaksson, M., Elfving, P., et al. 2006. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes, Chromosomes & Cancer 45:717–719.CrossRefGoogle Scholar
  51. Stegmaier, K., Wong, J.S., Ross, K.N., et al. 2007. Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Medicine 4:e122.PubMedCrossRefGoogle Scholar
  52. Tantivejkul, K., Loberg, R.D., Mawocha, S.C., et al. 2005. PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism. Journal of Cellular Biochemistry 96:641–652.PubMedCrossRefGoogle Scholar
  53. Thalmann, G.N., Anezinis, P.E., Chang, S.M., et al. 1994. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Research 54:2577–2581.PubMedGoogle Scholar
  54. Tomlins, S.A., Rhodes, D.R., Perner, S., et al. 2005. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–648.PubMedCrossRefGoogle Scholar
  55. Tomlins, S.A., Mehra, R., Rhodes, D.R., et al. 2006. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Research 66:3396–3400.PubMedCrossRefGoogle Scholar
  56. Tomlins, S.A., Laxman, B., Dhanasekaran, S.M., et al. 2007a. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448:595–599.CrossRefGoogle Scholar
  57. Tomlins, S.A., Mehra, R., Rhodes, D.R., et al. 2007b. Integrative molecular concept modeling of prostate cancer progression. Nature Genetics 39:41–51.CrossRefGoogle Scholar
  58. Tomlins, S.A., Laxman, B., Varambally, R., et al. 2008. The role of the TMPRSS2-ERG gene fusions in prostate cancer. Neoplasia 10:177–188.PubMedCrossRefGoogle Scholar
  59. Tu, J.J., Rohan, S., Kao, J., et al. 2007. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues. Modern Pathology 20:921–928.PubMedCrossRefGoogle Scholar
  60. Wang, J., Cai, Y., Ren, C., et al. 2006. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Research 66:8347–8351.PubMedCrossRefGoogle Scholar
  61. Wang, Q., Li, W., Liu, X.S.X., et al. 2007. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Molecular Cell 27:380–392.PubMedCrossRefGoogle Scholar
  62. Welsh, J.B., Sapinoso, L.M., Su, A.I., et al. 2001. Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancer. Cancer Research 61:5974–5978.PubMedGoogle Scholar
  63. Wilson, S., Greer, B., Hooper, J., et al. 2005. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. The Biochemical Journal 388:967–972.PubMedCrossRefGoogle Scholar
  64. van Bokhoven, A., Caires, A., Maria, M.D., et al. 2003. Spectral karyotype (SKY) analysis of human prostate carcinoma cell lines. The Prostate 57:226–244.PubMedCrossRefGoogle Scholar
  65. Winnes, M., Lissbrant, E., Damber, J.E., et al. 2007. Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer. Oncology Reports 17:1033–1036.PubMedGoogle Scholar
  66. Yin, Y.J., Salah, Z., Maoz, M., et al. 2003. Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. FASEB Journal 17:163–174.PubMedCrossRefGoogle Scholar
  67. Yu, Y.P., Landsittel, D., Jing, L., et al. 2004. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. Journal of Clinical Oncology 22:2790–2799.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Rou Wang
  • Scott A. Tomlins
  • Arul M. Chinnaiyan
    • 1
  1. 1.Department of Pathology and UrologyUniversity of MichiganAnn Arbor, MIUSA

Personalised recommendations