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Wnt/β-Catenin activation promotes prostate tumor progression in a mouse model

Abstract

Our previous studies have found that activation of Wnt/β-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB–Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/β-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear β-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/β-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/β-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB–Tag/dominant active (DA) β-catenin prostates, MMP7, a Wnt/β-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB–Tag/DA β-catenin mice. Although β-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB–Tag/DA β-catenin mice. Histological analysis shows that prostate sections derived from the LPB–Tag/DA β-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/β-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.

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Abbreviations

PCa:

prostate cancer

AR:

androgen receptor

HGPIN:

high-grade prostatic intraepithelial neoplasia

Tag:

large T-antigen

NE:

neuroendocrine

References

  • Barth AI, Stewart DB, Nelson WJ . (1999). T cell factor-activated transcription is not sufficient to induce anchorage-independent growth of epithelial cells expressing mutant beta-catenin. Proc Natl Acad Sci USA 96: 4947–4952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P et al. (1999). Roles for Nkx3.1 in prostate development and cancer. Genes Dev 13: 966–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonfil RD, Chinni S, Fridman R, Kim HR, Cher ML . (2007). Proteases, growth factors, chemokines, and the microenvironment in prostate cancer bone metastasis. Urol Oncol 25: 407–411.

    Article  CAS  PubMed  Google Scholar 

  • Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A et al. (2005). Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 179: 56–65.

    Article  CAS  PubMed  Google Scholar 

  • Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA et al. (2001). Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98: 10356–10361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruxvoort KJ, Charbonneau HM, Giambernardi TA, Goolsby JC, Qian CN, Zylstra CR et al. (2007). Inactivation of apc in the mouse prostate causes prostate carcinoma. Cancer Res 67: 2490–2496.

    Article  CAS  PubMed  Google Scholar 

  • Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS . (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310: 1504–1510.

    Article  CAS  PubMed  Google Scholar 

  • Chesire DR, Ewing CM, Gage WR, Isaacs WB . (2002). In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene 21: 2679–2694.

    Article  CAS  PubMed  Google Scholar 

  • Chesire DR, Ewing CM, Sauvageot J, Bova GS, Isaacs WB . (2000). Detection and analysis of beta-catenin mutations in prostate cancer. Prostate 45: 323–334.

    Article  CAS  PubMed  Google Scholar 

  • Crawford HC, Fingleton B, Gustavson MD, Kurpios N, Wagenaar RA, Hassell JA et al. (2001). The PEA3 subfamily of Ets transcription factors synergizes with beta-catenin-LEF-1 to activate matrilysin transcription in intestinal tumors. Mol Cell Biol 21: 1370–1383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la TA, Rubin MA, Chen MW, Vacherot F, de Medina SG, Burchardt M et al. (2003). Beta-catenin-related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells. Clin Cancer Res 9: 1801–1807.

    Google Scholar 

  • Deeb KK, Michalowska AM, Yoon CY, Krummey SM, Hoenerhoff MJ, Kavanaugh C et al. (2007). Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis. Cancer Res 67: 8065–8080.

    Article  CAS  PubMed  Google Scholar 

  • Fingleton B . (2006). Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci 11: 479–491.

    Article  CAS  PubMed  Google Scholar 

  • Gupta A, Wang Y-Q, Browne C, Kim S, Case TC, Paul M et al. (2008). Neuroendocrine differentiation in the 12T-10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells. Prostate 68: 50–60.

    Article  CAS  PubMed  Google Scholar 

  • Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M et al. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 18: 5931–5942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang D, Du X . (2008). Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 14: 1823–1827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huss WJ, Gray DR, Tavakoli K, Marmillion ME, Durham LE, Johnson MA et al. (2007). Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model. Neoplasia 9: 938–950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kasper S . (2005). Survey of genetically engineered mouse models for prostate cancer: analyzing the molecular basis of prostate cancer development, progression, and metastasis. J Cell Biochem 94: 279–297.

    Article  CAS  PubMed  Google Scholar 

  • Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS et al. (1998). Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer. Lab Invest 78: 319–334.

    CAS  PubMed  Google Scholar 

  • Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM et al. (2002). Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci USA 99: 2884–2889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klezovitch O, Chevillet J, Mirosevich J, Roberts RL, Matusik RJ, Vasioukhin V . (2004). Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6: 185–195.

    Article  CAS  PubMed  Google Scholar 

  • Lamberti C, Lin KM, Yamamoto Y, Verma U, Verma IM, Byers S et al. (2001). Regulation of beta-catenin function by the IkappaB kinases. J Biol Chem 276: 42276–42286.

    Article  CAS  PubMed  Google Scholar 

  • Levine AJ, Momand J . (1990). Tumor suppressor genes: the p53 and retinoblastoma sensitivity genes and gene products. Biochim Biophys Acta 1032: 119–136.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Miller JR . (2002). The Wnts. Genome Biol 3: 1–15.

    Google Scholar 

  • Mirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ . (2006). Expression and role of Foxa proteins in prostate cancer. Prostate 66: 1013–1029.

    Article  CAS  PubMed  Google Scholar 

  • Mirosevich J, Gao N, Matusik RJ . (2005). Expression of Foxa transcription factors in the developing and adult murine prostate. Prostate 62: 339–352.

    Article  CAS  PubMed  Google Scholar 

  • Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S . (2001). Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. J Cell Biol 153: 1161–1174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polakis P . (2000). Wnt signaling and cancer. Genes Dev 14: 1837–1851.

    CAS  PubMed  Google Scholar 

  • Qi J, Nakayama K, Cardiff RD, Borowsky AD, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sciarra A, Mariotti G, Gentile V, Voria G, Pastore A, Monti S et al. (2003). Neuroendocrine differentiation in human prostate tissue: is it detectable and treatable? BJU Int 91: 438–445.

    Article  CAS  PubMed  Google Scholar 

  • Song Z, Wu X, Powell WC, Cardiff RD, Cohen MB, Tin RT et al. (2002). FGF8, Isoform b overexpression in prostate epithelium: A new mouse model for prostatic intraepithelial neoplasia. Cancer Res 62: 5096–5105.

    CAS  PubMed  Google Scholar 

  • Terry S, Yang X, Chen MW, Vacherot F, Buttyan R . (2006). Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. J Cell Biochem 99: 402–410.

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Epstein JI . (2008). Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol 32: 65–71.

    Article  PubMed  Google Scholar 

  • Wang Y-Q, Kasper S, Yuan J, Jin RJ, Zhang J, Ishii K et al. (2006). Androgen dependent prostatic epithelial cell selection by targeting ARR2PBNeo to the LPB-Tag transgenic model of prostate cancer. Lab Invest 86: 1074–1088.

    Article  CAS  PubMed  Google Scholar 

  • Wilson CL, Matrisian LM . (1996). Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol 28: 123–136.

    Article  CAS  PubMed  Google Scholar 

  • Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M et al. (2003). WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol 201: 204–212.

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Wu J, Huang J, Powell WC, Zhang J, Matusik RJ et al. (2001). Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev 101: 61–69.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL et al. (2005). A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res 65: 5263–5271.

    Article  CAS  PubMed  Google Scholar 

  • Yao JL, Madeb R, Bourne P, Lei J, Yang X, Tickoo S et al. (2006). Small cell carcinoma of the prostate: an immunohistochemical study. Am J Surg Pathol 30: 705–712.

    Article  PubMed  Google Scholar 

  • Yardy GW, Brewster SF . (2005). Wnt signalling and prostate cancer. Prostate Cancer Prostatic Dis 8: 119–126.

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Gupta A, Wang Y-Q, Suzuki K, Mirosevich J, Orgebin-Crist MC et al. (2005). Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially. Ann N Y Acad Sci 1061: 77–93.

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Wang Y-Q, Jiang M, Bierie BB, Hayward SW, Shen MM et al. (2009). Activated beta-catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate 69: 249–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Chen MW, Ng A, Ng PY, Lee C, Rubin M et al. (1997). Abnormal Prostate Development in C3(1)-bcl-2 Transgenic Mice. Prostate 32: 16–26.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Angela Barth, the Stanford University, for kindly providing the mutant β-catenin expressing vector, Tom Case and Manik Paul for technical support, Dr Barbara Fingleton and Dr Lynn Matrisian for advice and discussion. Grant support was provided by NIH to RJM (Grant Numbers: 2R01 CA76142-11; 2R01-DK055748-10), DOD to RJM (Grant Number: PC074022), and the Joe C. Davis Foundation. David DeGraff, PhD was supported by the American Cancer Society Great Lakes Division-Michigan Cancer Research Fund Postdoctoral Fellowship.

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Correspondence to R J Matusik.

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Yu, X., Wang, Y., DeGraff, D. et al. Wnt/β-Catenin activation promotes prostate tumor progression in a mouse model. Oncogene 30, 1868–1879 (2011). https://doi.org/10.1038/onc.2010.560

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