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Mouse models of prostate cancer: picking the best model for the question

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Abstract

When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for “prostate cancer mouse model” yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin promoter driving viral oncogenes such as Simian virus 40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and overexpression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question?

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References

  1. Howlader, N., Noone, A., Krapcho, M., Garshell, J., Neyman, N., Altekruse, S., Kosary, C., Yu, M., Ruhl, J., Tatalovich, Z., Cho, H., Mariotto, A., Lewis, D., Chen, H., Feuer, E. (1975–2010). SEER Cancer Statistics Review, National Cancer Institute. Available from URL: http://seer.cancer.gov/csr/1975_2010/. Accessed 2 June 2013.

  2. Surveillance, Epidemiology, and End Results (SEER). SEER Stat Fact Sheets: Prostate. Available from URL: http://seer.cancer.gov/statfacts/html/prost.html. Accessed May 2013.

  3. Miller, A. B. (2012). New data on prostate-cancer mortality after PSA screening. New England Journal of Medicine, 366, 1047–1048.

    CAS  PubMed  Google Scholar 

  4. Stanford, J., Stephenson, R., Coyle, L., Cerhan, J., Correa, R., Eley, J., et al. (1999). Survival. Prostate cancer trends, 1973–1995. Bethesda: SEER Program, National Cancer Institute.

    Google Scholar 

  5. Suwa, T., Nyska, A., Haseman, J. K., Mahler, J. F., & Maronpot, R. R. (2002). Spontaneous lesions in control B6C3F1 mice and recommended sectioning of male accessory sex organs. Toxicologic Pathology, 30, 228–234.

    PubMed  Google Scholar 

  6. Vis, A. N., & Schröder, F. H. (2009). Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways. BJU International, 104, 438–448.

    CAS  PubMed  Google Scholar 

  7. Sun, Y., Niu, J., & Huang, J. (2009). Neuroendocrine differentiation in prostate cancer. American Journal of Translation Research, 1, 148–162.

    CAS  Google Scholar 

  8. Morrissey, C., & Vessella, R. L. (2007). The role of tumor microenvironment in prostate cancer bone metastasis. Journal of Cellular Biochemistry, 101, 873–886.

    CAS  PubMed  Google Scholar 

  9. Shappell, S. B., Thomas, G. V., Roberts, R. L., Herbert, R., Ittmann, M. M., Rubin, M. A., et al. (2004). Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Research, 64, 2270–2305.

    CAS  PubMed  Google Scholar 

  10. Ittmann, M., Huang, J., Radaelli, E., Martin, P., Signoretti, S., Sullivan, R., et al. (2013). Animal models of human prostate cancer: the consensus report of the New York meeting of the Mouse Models of Human Cancers Consortium Prostate Pathology Committee. Cancer Research, 73, 2718–2736.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Ousset, M., Van Keymeulen, A., Bouvencourt, G., Sharma, N., Achouri, Y., Simons, B. D., et al. (2012). Multipotent and unipotent progenitors contribute to prostate postnatal development. Nature Cell Biology, 14, 1131–1138.

    CAS  PubMed  Google Scholar 

  12. Liu, J., Pascal, L. E., Isharwal, S., Metzger, D., Ramos Garcia, R., Pilch, J., et al. (2011). Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Molecular Endocrinology, 25, 1849–1857.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Choi, N., Zhang, B., Zhang, L., Ittmann, M., & Xin, L. (2012). Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell, 21, 253–265.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Lu, T.-L., Huang, Y.-F., You, L.-R., Chao, N.-C., Su, F.-Y., Chang, J.-L., et al. (2013). Conditionally ablated Pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. The American Journal of Pathology, 182, 975–991.

    CAS  PubMed  Google Scholar 

  15. Wang, Z. A., Mitrofanova, A., Bergren, S. K., Abate-Shen, C., Cardiff, R. D., Califano, A., et al. (2013). Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nature Cell Biology, 15, 274–283.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Hu, Y., Ippolito, J. E., Garabedian, E. M., Humphrey, P. A., & Gordon, J. I. (2002). Molecular characterization of a metastatic neuroendocrine cell cancer arising in the prostates of transgenic mice. Journal of Biological Chemistry, 277, 44462–44474.

    CAS  PubMed  Google Scholar 

  17. Garabedian, E. M., Humphrey, P. A., & Gordon, J. I. (1998). A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proceedings of the National Academy of Sciences of the United States of America, 95, 15382–15387.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Chokkalingam, A. P., Nyrén, O., Johansson, J.-E., Gridley, G., McLaughlin, J. K., Adami, H.-O., et al. (2003). Prostate carcinoma risk subsequent to diagnosis of benign prostatic hyperplasia. Cancer, 98, 1727–1734.

    PubMed  Google Scholar 

  19. Bostwick, D. G., Liu, L., Brawer, M. K., & Qian, J. (2004). High-grade prostatic intraepithelial neoplasia. Revista de Urología, 6, 171–179.

    Google Scholar 

  20. Reyes, A., Swanson, P. E., Carbone, J. M., & Humphrey, P. A. (1997). Unusual histologic types of high-grade prostatic intraepithelial neoplasia. The American Journal of Surgical Pathology, 21, 1215–1222.

    CAS  PubMed  Google Scholar 

  21. Gingrich, J. R., Barrios, R. J., Foster, B. A., & Greenberg, N. M. (1999). Pathologic progression of autochthonous prostate cancer in the TRAMP model. Prostate Cancer and Prostatic Disease, 2, 70–75.

    Google Scholar 

  22. Park, J.-H., Walls, J. E., Galvez, J. J., Kim, M., Abate-Shen, C., Shen, M. M., et al. (2002). Prostatic intraepithelial neoplasia in genetically engineered mice. The American Journal of Pathology, 161, 727–735.

    PubMed Central  PubMed  Google Scholar 

  23. Humphrey, P. A. (2012). Histological variants of prostatic carcinoma and their significance. Histopathology, 60, 59–74.

    PubMed  Google Scholar 

  24. Wang, W., & Epstein, J. I. (2008). Small cell carcinoma of the prostate: a morphologic and immunohistochemical study of 95 cases. The American Journal of Surgical Pathology, 32, 65–71.

    PubMed  Google Scholar 

  25. Palmgren, J. S., Karavadia, S. S., & Wakefield, M. R. (2007). Unusual and underappreciated: small cell carcinoma of the prostate. Seminar in Oncology, 34, 22–29.

    CAS  Google Scholar 

  26. Hansel, D. E., & Epstein, J. I. (2006). Sarcomatoid carcinoma of the prostate: a study of 42 cases. American Journal of Surgical Pathology, 30, 1316–1321.

    PubMed  Google Scholar 

  27. Martin, P., Liu, Y.-N., Pierce, R., Abou-Kheir, W., Casey, O., Seng, V., et al. (2011). Prostate epithelial Pten/TP53 loss leads to transformation of multipotential progenitors and epithelial to mesenchymal transition. The American Journal of Pathology, 179, 422–435.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Acevedo, V. D., Gangula, R. D., Freeman, K. W., Li, R., Zhang, Y., Wang, F., et al. (2007). Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell, 12, 559–571.

    CAS  PubMed  Google Scholar 

  29. Mulholland, D. J., Kobayashi, N., Ruscetti, M., Zhi, A., Tran, L. M., Huang, J., et al. (2012). Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Research, 72, 1878–1889.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Vinall, R. L., Chen, J. Q., Hubbard, N. E., Sulaimon, S. S., Shen, M. M., DeVere White, R. W., et al. (2012). Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression. Disease Models & Mechanisms, 5, 914–920.

    CAS  Google Scholar 

  31. Ayala, G. E., Muezzinoglu, B., Hammerich, K. H., Frolov, A., Liu, H., Scardino, P. T., et al. (2011). Determining prostate cancer-specific death through quantification of stromogenic carcinoma area in prostatectomy specimens. The American Journal of Pathology, 178, 79–87.

    PubMed Central  PubMed  Google Scholar 

  32. Ayala, G., Tuxhorn, J. A., Wheeler, T. M., Frolov, A., Scardino, P. T., Ohori, M., et al. (2003). Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clinical Cancer Research, 9, 4792–4801.

    CAS  PubMed  Google Scholar 

  33. Hayward, S. W., Wang, Y., Cao, M., Hom, Y. K., Zhang, B., Grossfeld, G. D., et al. (2001). Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Research, 61, 8135–8142.

    CAS  PubMed  Google Scholar 

  34. Small, E. J., Schellhammer, P. F., Higano, C. S., Redfern, C. H., Nemunaitis, J. J., Valone, F. H., et al. (2006). Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic. Asymptomatic hormone refractory prostate cancer. Journal of Clinical Oncology, 24, 3089–3094.

    CAS  PubMed  Google Scholar 

  35. Hess, K. R., Varadhachary, G. R., Taylor, S. H., Wei, W., Raber, M. N., Lenzi, R., et al. (2006). Metastatic patterns in adenocarcinoma. Cancer, 106, 1624–1633.

    PubMed  Google Scholar 

  36. Nandana, S., Ellwood-Yen, K., Sawyers, C., Wills, M., Weidow, B., Case, T., et al. (2010). Hepsin cooperates with MYC in the progression of adenocarcinoma in a prostate cancer mouse model. The Prostate, 70, 591–600.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Ding, Z., Wu, C.-J., Jaskelioff, M., Ivanova, E., Kost-Alimova, M., Protopopov, A., et al. (2012). Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell, 148, 896–907.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Gingrich, J. R., Barrios, R. J., Morton, R. A., Boyce, B. F., DeMayo, F. J., Finegold, M. J., et al. (1996). Metastatic prostate cancer in a transgenic mouse. Cancer Research, 56, 4096–4102.

    CAS  PubMed  Google Scholar 

  39. Prostate Cancer Trialists' Collaborative G. (1995). Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. The Lancet, 346, 265–269.

    Google Scholar 

  40. Scher, H. I., Fizazi, K., Saad, F., Taplin, M.-E., Sternberg, C. N., Miller, K., et al. (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine, 367, 1187–1197.

    CAS  PubMed  Google Scholar 

  41. Fizazi, K., Scher, H. I., Molina, A., Logothetis, C. J., Chi, K. N., Jones, R. J., et al. (2012). Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. The Lancet Oncology, 13, 983–992.

    CAS  PubMed  Google Scholar 

  42. Greenberg, N. M., DeMayo, F. J., Sheppard, P. C., Barrios, R., Lebovitz, R., Finegold, M., et al. (1994). The rat probasin gene promoter directs hormonally and developmentally regulated expression of a heterologous gene specifically to the prostate in transgenic mice. Molecular Endocrinology, 8, 230–239.

    CAS  PubMed  Google Scholar 

  43. Bhatia-Gaur, R., Donjacour, A. A., Sciavolino, P. J., Kim, M., Desai, N., Young, P., et al. (1999). Roles for Nkx3.1 in prostate development and cancer. Genes and Development, 13, 966–977.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Tanaka, M., Komuro, I., Inagaki, H., Jenkins, N. A., Copeland, N. G., & Izumo, S. (2000). Nkx3.1, a murine homolog of Drosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Developmental Dynamics, 219, 248–260.

    CAS  PubMed  Google Scholar 

  45. Rennie, P. S., Bruchovsky, N., Leco, K. J., Sheppard, P. C., McQueen, S. A., Cheng, H., et al. (1993). Characterization of two cis-acting DNA elements involved in the androgen regulation of the probasin gene. Molecular Endocrinology, 7, 23–36.

    CAS  PubMed  Google Scholar 

  46. Zhang, J., Thomas, T. Z., Kasper, S., & Matusik, R. J. (2000). A small composite probasin promoter confers high levels of prostate-specific gene expression through regulation by androgens and glucocorticoids in vitro and in vivo. Endocrinology, 141, 4698–4710.

    CAS  PubMed  Google Scholar 

  47. Bianchi-Frias, D., Pritchard, C., Mecham, B., Coleman, I., & Nelson, P. (2007). Genetic background influences murine prostate gene expression: implications for cancer phenotypes. Genome Biology, 8, R117.

    PubMed Central  PubMed  Google Scholar 

  48. Chiaverotti, T., Couto, S. S., Donjacour, A., Mao, J.-H., Nagase, H., Cardiff, R. D., et al. (2008). Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. The American journal of pathology, 172, 236–246.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Ahuja, D., Saenz-Robles, M. T., & Pipas, J. M. (2005). SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene, 24, 7729–7745.

    CAS  PubMed  Google Scholar 

  50. Maroulakou, I. G., Anver, M., Garrett, L., & Green, J. E. (1994). Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proceedings of the National Academy of Sciences of the United States of America, 91, 11236–11240.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Greenberg, N. M., DeMayo, F., Finegold, M. J., Medina, D., Tilley, W. D., Aspinall, J. O., et al. (1995). Prostate cancer in a transgenic mouse. Proceedings of the National Academy of Sciences of the United States of America, 92, 3439–3443.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Gingrich, J. R., Barrios, R. J., Kattan, M. W., Nahm, H. S., Finegold, M. J., & Greenberg, N. M. (1997). Androgen-independent prostate cancer progression in the TRAMP model. Cancer Research, 57, 4687–4691.

    CAS  PubMed  Google Scholar 

  53. Kaplan-Lefko, P. J., Chen, T.-M., Ittmann, M. M., Barrios, R. J., Ayala, G. E., Huss, W. J., et al. (2003). Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. The Prostate, 55, 219–237.

    PubMed  Google Scholar 

  54. Han, G., Foster, B. A., Mistry, S., Buchanan, G., Harris, J. M., Tilley, W. D., et al. (2001). Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in autochthonous prostate cancer. Journal of Biological Chemistry, 276, 11204–11213.

    CAS  PubMed  Google Scholar 

  55. Irshad, S., & Abate-Shen, C. (2012). Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic. Cancer and Metastasis Reviews, 32, 1–14.

    Google Scholar 

  56. Ahmad, I., Sansom, O. J., & Leung, H. Y. (2009). The role of murine models of prostate cancer in drug target discovery and validation. Expert Opinion on Drug Discovery, 4, 879–888.

    CAS  PubMed  Google Scholar 

  57. Kasper, S., Sheppard, P. C., Yan, Y., Pettigrew, N., Borowsky, A. D., Prins, G., et al. (1998). Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer. Laboratory Investigation, 78, i–xv.

    CAS  PubMed  Google Scholar 

  58. Klezovitch, O., Chevillet, J., Mirosevich, J., Roberts, R. L., Matusik, R. J., & Vasioukhin, V. (2004). Hepsin promotes prostate cancer progression and metastasis. Cancer Cell, 6, 185–195.

    CAS  PubMed  Google Scholar 

  59. Masumori, N., Thomas, T. Z., Chaurand, P., Case, T., Paul, M., Kasper, S., et al. (2001). A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential. Cancer Research, 61, 2239–2249.

    CAS  PubMed  Google Scholar 

  60. Palmer, J., Venkateswaran, V., Fleshner, N. E., Klotz, L. H., & Cox, M. E. (2008). The impact of diet and micronutrient supplements on the expression of neuroendocrine markers in murine Lady transgenic prostate. The Prostate, 68, 345–353.

    CAS  PubMed  Google Scholar 

  61. Venkateswaran, V., Klotz, L. H., Ramani, M., Sugar, L. M., Jacob, L. E., Nam, R. K., et al. (2009). A combination of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the Lady transgenic model. Cancer Prev Res (Phila Pa), 2, 473–483.

    CAS  Google Scholar 

  62. Guo, Y., Jacobs, S. C., & Kyprianou, N. (1997). Down-regulation of protein and mRNA expression for transforming growth factor-β (TGF-β1) type I and type II receptors in human prostate cancer. International Journal of Cancer, 71, 573–579.

    CAS  Google Scholar 

  63. Tu, W. H., Thomas, T., Masumori, N., Bhowmick, N., Gorska, A., Shyr, Y., et al. (2003). The loss of TGF-β signaling promotes prostate cancer metastasis. Neoplasia, 5, 267–277.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Yu, X., Wang, Y., DeGraff, D. J., Wills, M. L., & Matusik, R. J. (2011). Wnt/Beta-catenin activation promotes prostate tumor progression in a mouse model. Oncogene, 30, 1868–1879.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Gounari, F., Signoretti, S., Bronson, R., Klein, L., Sellers, W. R., Kum, J., et al. (2002). Stabilization of b-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdiferentiation of other secretory epithelia. Oncogene, 21, 4099–4107.

    CAS  PubMed  Google Scholar 

  66. Bruxvoort, K. J., Charbonneau, H. M., Giambernardi, T. A., Goolsby, J. C., Qian, C.-N., Zylstra, C. R., et al. (2007). Inactivation of Apc in the mouse prostate causes prostate carcinoma. Cancer Research, 67, 2490–2496.

    CAS  PubMed  Google Scholar 

  67. Zhou, Z., Flesken-Nikitin, A., Corney, D. C., Wang, W., Goodrich, D. W., Roy-Burman, P., et al. (2006). Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Research, 66, 7889–7898.

    CAS  PubMed  Google Scholar 

  68. Hill, R., Song, Y., Cardiff, R. D., & Van Dyke, T. (2005). Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model. Cancer Research, 65, 10243–10254.

    CAS  PubMed  Google Scholar 

  69. Phillips, S. M., Barton, C. M., Lee, S. J., Morton, D. G., Wallace, D. M., Lemoine, N. R., et al. (1994). Loss of the retinoblastoma susceptibility gene (RB1) is a frequent and early event in prostatic tumorigenesis. British Journal of Cancer, 70, 1252–1257.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Bookstein, R., MacGrogan, D., Hilsenbeck, S. G., Sharkey, F., & Allred, D. C. (1993). p53 is mutated in a subset of advanced-stage prostate cancers. Cancer Research, 53, 3369–3373.

    CAS  PubMed  Google Scholar 

  71. Saric, T., Brkanac, Z., Troyer, D. A., Padalecki, S. S., Sarosdy, M., Williams, K., et al. (1999). Genetic pattern of prostate cancer progression. International Journal of Cancer, 81, 219–224.

    CAS  Google Scholar 

  72. Qi, J., Nakayama, K., Cardiff, R. D., Borowsky, A. D., Kaul, K., Williams, R., et al. (2010). Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell, 18, 23–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Spence, A. M., Sheppard, P. C., Davie, J. R., Matuo, Y., Nishi, N., McKeehan, W. L., et al. (1989). Regulation of a bifunctional mRNA results in synthesis of secreted and nuclear probasin. Proceedings of the National Academy of Sciences of the United States of America, 86, 7843–7847.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Maddison, L. A., Nahm, H., DeMayo, F., & Greenberg, N. M. (2000). Prostate specific expression of Cre recombinase in transgenic mice. Genesis, 26, 154–156.

    CAS  PubMed  Google Scholar 

  75. Wu, X., Wu, J., Huang, J., Powell, W. C., Zhang, J., Matusik, R. J., et al. (2001). Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mechanisms of Development, 101, 61–69.

    CAS  PubMed  Google Scholar 

  76. Song, M. S., Salmena, L., & Pandolfi, P. P. (2012). The functions and regulation of the PTEN tumour suppressor. Nature Reviews in Molecular and Cell Biology, 13, 283–296.

    CAS  Google Scholar 

  77. Cantley, L. C., & Neel, B. G. (1999). New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proceedings of the National Academy of Sciences of the United States of America, 96, 4240–4245.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Yoshimoto, M., Cutz, J.-C., Nuin, P. A. S., Joshua, A. M., Bayani, J., Evans, A. J., et al. (2006). Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68 % of primary prostate cancer and 23 % of high-grade prostatic intra-epithelial neoplasias. Cancer Genetics and Cytogenetics, 169, 128–137.

    CAS  PubMed  Google Scholar 

  79. Holcomb, I. N., Young, J. M., Coleman, I. M., Salari, K., Grove, D. I., Hsu, L., et al. (2009). Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. Cancer Research, 69, 7793–7802.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Cristofano, A. D., Pesce, B., Cordon-Cardo, C., & Pandolfi, P. P. (1998). Pten is essential for embryonic development and tumour suppression. Nature Genetics, 19, 348–355.

    PubMed  Google Scholar 

  81. Suzuki, A., de la Pompa, J. L., Stambolic, V., Elia, A. J., Sasaki, T., Barrantes, I. D. B., et al. (1998). High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Current biology, CB 8, 1169–1178.

    Google Scholar 

  82. Podsypanina, K., Ellenson, L. H., Nemes, A., Gu, J., Tamura, M., Yamada, K. M., et al. (1999). Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proceedings of the National Academy of Sciences of the United States of America, 96, 1563–1568.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Trotman, L. C., Niki, M., Dotan, Z. A., Koutcher, J. A., Di Cristofano, A., Xiao, A., et al. (2003). Pten dose dictates cancer progression in the prostate. PLoS Biology, 1, e59.

    PubMed Central  PubMed  Google Scholar 

  84. Stambolic, V., Tsao, M.-S., Macpherson, D., Suzuki, A., Chapman, W. B., & Mak, T. W. (2000). High incidence of breast and endometrial neoplasia resembling human cowden syndrome in Pten+/− mice. Cancer Research, 60, 3605–3611.

    CAS  PubMed  Google Scholar 

  85. Vis, A. N., Noordzij, M. A., Fitoz, K., Wildhagen, M. F., Schroder, F. H., & van der Kwast, T. H. (2000). Prognostic value of cell cycle proteins p27kip1 and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer. The Journal of Urology, 164, 2156–2161.

    CAS  PubMed  Google Scholar 

  86. Cordon-Cardo, C., Koff, A., Drobnjak, M., Capodieci, P., Osman, I., Millard, S. S., et al. (1998). Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. Journal of the National Cancer Institute, 90, 1284–1291.

    CAS  PubMed  Google Scholar 

  87. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., & Pandolfi, P. P. (2001). Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nature Genetics, 27, 222–224.

    PubMed  Google Scholar 

  88. Sciavolino, P. J., Abrams, E. W., Yang, L., Austenberg, L. P., Shen, M. M., & Abate-Shen, C. (1997). Tissue-specific expression of murine Nkx3.1 in the male urogenital system. Developmental Dynamics, 209, 127–138.

    CAS  PubMed  Google Scholar 

  89. Kim, M. J., Cardiff, R. D., Desai, N., Banach-Petrosky, W. A., Parsons, R., Shen, M. M., et al. (2002). Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 99, 2884–2889.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Bowen, C., Bubendorf, L., Voeller, H. J., Slack, R., Willi, N., Sauter, G., et al. (2000). Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Research, 60, 6111–6115.

    CAS  PubMed  Google Scholar 

  91. Schneider, A., Brand, T., Zweigerdt, R., & Arnold, H.-H. (2000). Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mechanisms of Development, 95, 163–174.

    CAS  PubMed  Google Scholar 

  92. Abdulkadir, S. A., Magee, J. A., Peters, T. J., Kaleem, Z., Naughton, C. K., Humphrey, P. A., et al. (2002). Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Molecular and Cellular Biology, 22, 1495–1503.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Kim, M. J., Bhatia-Gaur, R., Banach-Petrosky, W. A., Desai, N., Wang, Y., Hayward, S. W., et al. (2002). Nkx3.1 mutant mice recapitulate early stages of prostate carcinogenesis. Cancer Research, 62, 2999–3004.

    CAS  PubMed  Google Scholar 

  94. Abate-Shen, C., Banach-Petrosky, W. A., Sun, X., Economides, K. D., Desai, N., Gregg, J. P., et al. (2003). Nkx3.1; pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Research, 63, 3886–3890.

    CAS  PubMed  Google Scholar 

  95. Wang, S., Gao, J., Lei, Q., Rozengurt, N., Pritchard, C., Jiao, J., et al. (2003). Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell, 4, 209–221.

    CAS  PubMed  Google Scholar 

  96. Waltering, K. K., Urbanucci, A., & Visakorpi, T. (2012). Androgen receptor (AR) aberrations in castration-resistant prostate cancer. Molecular and Cellular Endocrinology, 360, 38–43.

    CAS  PubMed  Google Scholar 

  97. Holzbeierlein, J., Lal, P., LaTulippe, E., Smith, A., Satagopan, J., Zhang, L., et al. (2004). Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. The American Journal of Pathology, 164, 217–227.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Visakorpi, T., Hyytinen, E., Koivisto, P., Tanner, M., Keinanen, R., Palmberg, C., et al. (1995). In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genetics, 9, 401–406.

    CAS  PubMed  Google Scholar 

  99. Liao, C.-P., Zhong, C., Saribekyan, G., Bading, J., Park, R., Conti, P. S., et al. (2007). Mouse models of prostate adenocarcinoma with the capacity to monitor spontaneous carcinogenesis by bioluminescence or fluorescence. Cancer Research, 67, 7525–7533.

    CAS  PubMed  Google Scholar 

  100. Zhang, W., Zhu, J., Efferson, C. L., Ware, C., Tammam, J., Angagaw, M., et al. (2009). Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-deficient mouse model of prostate cancer. Cancer Research, 69, 7466–7472.

    CAS  PubMed  Google Scholar 

  101. Mulholland David, J., Tran Linh, M., Li, Y., Cai, H., Morim, A., Wang, S., et al. (2011). Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell, 19, 792–804.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., et al. (2005). Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature, 436, 725–730.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Ma, X., der Made AC, Z.-v., Autar, B., van der Korput, H. A., Vermeij, M., van Duijn, P., et al. (2005). Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. Cancer Research, 65, 5730–5739.

    CAS  PubMed  Google Scholar 

  104. Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Medicine, 10, 594–601.

    CAS  PubMed  Google Scholar 

  105. Ratnacaram, C. K., Teletin, M., Jiang, M., Meng, X., Chambon, P., & Metzger, D. (2008). Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 105, 2521–2526.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Wang, X., Julio, M. K.-d., Economides, K. D., Walker, D., Yu, H., Halili, M. V., et al. (2009). A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature, 461, 495–500.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Floc'h, N., Kinkade, C. W., Kobayashi, T., Aytes, A., Lefebvre, C., Mitrofanova, A., et al. (2012). Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Research, 72, 4483–4493.

    PubMed Central  PubMed  Google Scholar 

  108. Dankort, D., Filenova, E., Collado, M., Serrano, M., Jones, K., & McMahon, M. (2007). A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes and Development, 21, 379–384.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Wang, J., Kobayashi, T., Floc'h, N., Kinkade, C. W., Aytes, A., Dankort, D., et al. (2012). B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Research, 72, 4765–4776.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Aytes, A., Mitrofanova, A., Kinkade, C. W., Lefebvre, C., Lei, M., Phelan, V., et al. (2013). ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 110, E3506–E3515.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P., & Witte, O. N. (2010). Identification of a cell of origin for human prostate cancer. Science, 329, 568–571.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Aitchison, A. A., Veerakumarasivam, A., Vias, M., Kumar, R., Hamdy, F. C., Neal, D. E., et al. (2008). Promoter methylation correlates with reduced Smad4 expression in advanced prostate cancer. The Prostate, 68, 661–674.

    CAS  PubMed  Google Scholar 

  113. Ding, Z., Wu, C.-J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., et al. (2011). SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature, 470, 269–273.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X.-W., et al. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 310, 644–648.

    CAS  PubMed  Google Scholar 

  115. Tomlins, S. A., Mehra, R., Rhodes, D. R., Smith, L. R., Roulston, D., Helgeson, B. E., et al. (2006). TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Research, 66, 3396–3400.

    CAS  PubMed  Google Scholar 

  116. Tomlins, S. A., Laxman, B., Dhanasekaran, S. M., Helgeson, B. E., Cao, X., Morris, D. S., et al. (2007). Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature, 448, 595–599.

    CAS  PubMed  Google Scholar 

  117. Klezovitch, O., Risk, M., Coleman, I., Lucas, J. M., Null, M., True, L. D., et al. (2008). A causal role for ERG in neoplastic transformation of prostate epithelium. Proceedings of the National Academy of Sciences of the United States of America, 105, 2105–2110.

    PubMed Central  PubMed  Google Scholar 

  118. Tomlins, S. A., Laxman, B., Varambally, S., Cao, X., Yu, J., Helgeson, B. E., et al. (2008). The role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia, 10, 177–188.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Carver, B. S., Tran, J., Gopalan, A., Chen, Z., Shaikh, S., Carracedo, A., et al. (2009). Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nature Genetics, 41, 619–624.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. King, J. C., Xu, J., Wongvipat, J., Hieronymus, H., Carver, B. S., Leung, D. H., et al. (2009). Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nature Genetics, 41, 524–526.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Baena, E., Shao, Z., Linn, D. E., Glass, K., Hamblen, M. J., Fujiwara, Y., et al. (2013). ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes and Development, 27, 683–698.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Yoshimoto, M., Joshua, A. M., Cunha, I. W., Coudry, R. A., Fonseca, F. P., Ludkovski, O., et al. (2008). Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Modern Pathology, 21, 1451–1460.

    CAS  PubMed  Google Scholar 

  123. Zhong, C., Saribekyan, G., Liao, C.-P., Cohen, M. B., & Roy-Burman, P. (2006). Cooperation between FGF8b overexpression and PTEN deficiency in prostate tumorigenesis. Cancer Research, 66, 2188–2194.

    CAS  PubMed  Google Scholar 

  124. Nguyen, A. H. T., Tremblay, M., Haigh, K., Koumakpayi, I. H., Paquet, M., Pandolfi, P. P., et al. (2013). Gata3 antagonizes cancer progression in Pten-deficient prostates. Human Molecular Genetics, 22, 2400–2410.

    CAS  PubMed  Google Scholar 

  125. Nacerddine, K., Beaudry, J.-B., Ginjala, V., Westerman, B., Mattiroli, F., Song, J.-Y., van der Poel, H., Ponz, O. B., Pritchard, C., Cornelissen-Steijger, P., Zevenhoven, J., Tanger, J., Sixma, E., Ganesan, T. K., & van Lohuizen, M. (2012). Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer. The Journal of Clinical Investigation, 122, 1920–1932.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Jackson, E. L., Willis, N., Mercer, K., Bronson, R. T., Crowley, D., Montoya, R., et al. (2001). Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes and Development, 15, 3243–3248.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Carver Brett, S., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., et al. (2011). Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell, 19, 575–586.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Svensson, R. U., Haverkamp, J. M., Thedens, D. R., Cohen, M. B., Ratliff, T. L., & Henry, M. D. (2011). Slow disease progression in a C57BL/6 Pten-deficient mouse model of prostate cancer. The American Journal of Pathology, 179, 502–512.

    PubMed Central  PubMed  Google Scholar 

  129. Gurel, B., Iwata, T., Koh, C. M., Jenkins, R. B., Lan, F., Van Dang, C., et al. (2008). Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Modern Pathology, 21, 1156–1167.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Fleming, W. H., Hamel, A., MacDonald, R., Ramsey, E., Pettigrew, N. M., Johnston, B., et al. (1986). Expression of the c-myc protooncogene in human prostatic carcinoma and benign prostatic hyperplasia. Cancer Research, 46, 1535–1538.

    CAS  PubMed  Google Scholar 

  131. Koh, C. M., Bieberich, C. J., Dang, C. V., Nelson, W. G., Yegnasubramanian, S., & De Marzo, A. M. (2010). MYC and prostate cancer. Genes & Cancer, 1, 617–628.

    CAS  Google Scholar 

  132. Ellwood-Yen, K., Graeber, T. G., Wongvipat, J., Iruela-Arispe, M. L., Zhang, J., Matusik, R., et al. (2003). Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell, 4, 223–238.

    CAS  PubMed  Google Scholar 

  133. Iwata, T., Schultz, D., Hicks, J., Hubbard, G. K., Mutton, L. N., Lotan, T. L., et al. (2010). MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PLoS ONE, 5, e9427.

    PubMed Central  PubMed  Google Scholar 

  134. Jin, R. J., Lho, Y., Connelly, L., Wang, Y., Yu, X., Saint Jean, L., et al. (2008). The nuclear factor-KappaB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Research, 68, 6762–6769.

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Clegg, N. J., Couto, S. S., Wongvipat, J., Hieronymus, H., Carver, B. S., Taylor, B. S., et al. (2011). MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors. PLoS ONE, 6, e17449.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Roh, M., Kim, J., Song, C., Wills, M., & Abdulkadir, S. A. (2006). Transgenic mice for Cre-inducible overexpression of the oncogenes c-MYC and Pim-1 in multiple tissues. Genesis, 44, 447–453.

    CAS  PubMed  Google Scholar 

  137. Kim, J., Roh, M., Doubinskaia, I., Algarroba, G. N., Eltoum, I.-E. A., & Abdulkadir, S. A. (2012). A mouse model of heterogeneous, c-MYC-initiated prostate cancer with loss of Pten and p53. Oncogene, 31, 322–332.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Hensley, P., & Kyprianou, N. (2012). Modeling prostate cancer in mice: limitations and opportunities. Journal of Andrology, 33, 133–144.

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Shen, M. M., & Abate-Shen, C. (2010). Molecular genetics of prostate cancer: new prospects for old challenges. Genes and Development, 24, 1967–2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Jeet, V., Russell, P., & Khatri, A. (2010). Modeling prostate cancer: a perspective on transgenic mouse models. Cancer and Metastasis Reviews, 29, 123–142.

    PubMed  Google Scholar 

  141. Marcus, D. M., Goodman, M., Jani, A. B., Osunkoya, A. O., & Rossi, P. J. (2012). A comprehensive review of incidence and survival in patients with rare histological variants of prostate cancer in the United States from 1973 to 2008. Prostate Cancer and Prostatic Disease, 15, 283–288.

    CAS  Google Scholar 

  142. Jin, R. J., Wang, Y., Masumori, N., Ishii, K., Tsukamoto, T., Shappell, S. B., et al. (2004). NE-10 neuroendocrine cancer promotes the LNCaP xenograft growth in castrated mice. Cancer Research, 64, 5489–5495.

    CAS  PubMed  Google Scholar 

  143. Stanbrough, M., Leav, I., Kwan, P. W. L., Bubley, G. J., & Balk, S. P. (2001). Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proceedings of the National Academy of Sciences of the United States of America, 98, 10823–10828.

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Albertelli, M. A., Scheller, A., Brogley, M., & Robins, D. M. (2006). Replacing the mouse androgen receptor with human alleles demonstrates glutamine tract length-dependent effects on physiology and tumorigenesis in mice. Molecular Endocrinology, 20, 1248–1260.

    CAS  PubMed  Google Scholar 

  145. Zhu, C., Luong, R., Zhuo, M., Johnson, D. T., McKenney, J. K., Cunha, G. R., et al. (2011). Conditional expression of the androgen receptor induces oncogenic transformation of the mouse prostate. Journal of Biological Chemistry, 286, 33478–33488.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Zhang, X., Morrissey, C., Sun, S., Ketchandji, M., Nelson, P. S., True, L. D., et al. (2011). Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS ONE, 6, e27970.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Sun, S., Sprenger, C. C. T., Vessella, R. L., Haugk, K., Soriano, K., Mostaghel, E. A., et al. (2010). Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. The Journal of Clinical Investigation, 120, 2715–2730.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Liu, G., Sprenger, C., Sun, S., Epilepsia, K. S., Haugk, K., Zhang, X., et al. (2013). AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia (NY), 15, 1009–1017.

    CAS  PubMed Central  Google Scholar 

  149. Cunha, G. R. (2008). Mesenchymal-epithelial interactions: past, present, and future. Differentiation, 76, 578–586.

    CAS  PubMed  Google Scholar 

  150. Ricke, E. A., Williams, K., Lee, Y.-F., Couto, S., Wang, Y., Hayward, S. W., et al. (2012). Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis. Carcinogenesis, 33, 1391–1398.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Lai, K.-P., Yamashita, S., Huang, C.-K., Yeh, S., & Chang, C. (2012). Loss of stromal androgen receptor leads to suppressed prostate tumourigenesis via modulation of pro-inflammatory cytokines/chemokines. EMBO Molecular Medicine, 4, 791–807.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Bhowmick, N., Chytil, A., Plieth, D., Gorska, A., Dumont, N., Shappell, S., et al. (2004). TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science, 303, 848–851.

    CAS  PubMed  Google Scholar 

  153. Li, X., Placencio, V., Iturregui, J. M., Uwamariya, C., Sharif-Afshar, A. R., Koyama, T., et al. (2008). Prostate tumor progression is mediated by a paracrine TGF-[beta]/Wnt3a signaling axis. Oncogene, 27, 7118–7130.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Franco, O. E., & Hayward, S. W. (2012). Chapter nine—targeting the tumor stroma as a novel therapeutic approach for prostate cancer. In S. M. S. Keiran (Ed.), Advances in pharmacology (pp. 267–313). Bethesda: Academic.

    Google Scholar 

  155. Beltran, H., Rickman, D. S., Park, K., Chae, S. S., Sboner, A., MacDonald, T. Y., et al. (2011). Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery, 1, 487–495.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Mosquera, J. M., Beltran, H., Park, K., MacDonald, T. Y., Robinson, B. D., Tagawa, S. T., et al. (2013). Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia, 15, 1–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Watson, P. A., Chen, Y. F., Balbas, M. D., Wongvipat, J., Socci, N. D., Viale, A., et al. (2010). Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proceedings of the National Academy of Sciences of the United States of America, 107, 16759–16765.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Crnalic, S., Hörnberg, E., Wikström, P., Lerner, U. H., Tieva, Å., Svensson, O., et al. (2010). Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients. Endocrine-Related Cancer, 17, 885–895.

    CAS  PubMed  Google Scholar 

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Acknowledgments

When selecting GEM models for this review, we have focused on selecting models which have been well characterized, frequently used, and of particular use to the PCa research field. Additionally, we have included certain models for their particular significance in utilizing novel human PCa lesions or unique approaches to tumorigenesis. Our hope is that this review will serve as a tool in selecting which model may be appropriate for a given research study. We would like to thank all researchers whose work we have cited, those whose contributions were omitted in the interest of space constraints, and those whose omission was unintentional. The brevity of this review is greatly attributable to the excellent and exhaustive reviews on mouse models [55, 138–140], mouse PCa pathology [9, 10], and human PCa progression [139] published previously.

MMG was supported by the VUMC Integrated Biological Systems Training in Oncology training grant (2 T32 CA119925-06). DJD was supported by an NIH Pathway to Independence Award (1 K99 CA172122), the VUMC Multidisciplinary Training Grant in Molecular Endocrinology (5 T32 DK007563-21), the VUMC Integrated Biological Systems Training in Oncology training grant (1 T32 CA119925), and the American Cancer Society Great Lakes Division-Michigan Cancer Research Fund Postdoctoral Fellowship. XY was supported by Department of Defense (DOD) PC111074. RJJ was supported by the DOD Prostate Cancer Research Program (W81XWH-10-1-0236). ZC was supported by the National Institute on Minority Health and Health Disparities grants MD 5 R01 004038, G12 MD 007586, and 5 U54 CA 163069. AB was supported by NCI (U01 CA141582) and the UC Davis Extension Genomic Pathology online course in Pathobiology of the Mouse (http://extension.ucdavis.edu/unit/health_sciences/pdf/114150_Genomic.pdf). RJM was supported by the NCI (R01-CA076142-14) and NIDDK (R01-DK055748-13).

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  1. Vanderbilt University, Nashville, TN, USA

    Magdalena M. Grabowska, David J. DeGraff, Xiuping Yu, Ren Jie Jin & Robert J. Matusik

  2. Meharry Medical College, Nashville, TN, USA

    Zhenbang Chen

  3. University of California Davis, Davis, CA, USA

    Alexander D. Borowsky

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  1. Magdalena M. Grabowska
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  2. David J. DeGraff
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  7. Robert J. Matusik
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Correspondence to Magdalena M. Grabowska.

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Grabowska, M.M., DeGraff, D.J., Yu, X. et al. Mouse models of prostate cancer: picking the best model for the question. Cancer Metastasis Rev 33, 377–397 (2014). https://doi.org/10.1007/s10555-013-9487-8

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