Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation

Oncogene volume 30, pages 178–189 (2011)Cite this article

Subjects

Abstract

Although deregulation of the Wnt signalling pathway has been implicated in urothelial cell carcinoma (UCC), the functional significance is unknown. To test its importance, we have targeted expression of an activated form of β-catenin to the urothelium of transgenic mice using Cre–Lox technology (UroIICRE+ β-cateninexon3/+). Expression of this activated form of β-catenin led to the formation of localized hyperproliferative lesions by 3 months, which did not progress to malignancy. These lesions were characterized by a marked increase of the phosphatase and tensin homologue (PTEN) tumour suppressor protein. This appears to be a direct consequence of activating Wnt signalling in the bladder as conditional deletion of the adenomatous polyposis coli (Apc) gene within the adult bladder led rapidly to coincident β-catenin and PTEN expression. This PTEN expression blocked proliferation. Next, we combined PTEN deficiency with β-catenin activation and found that this caused papillary UCC. These tumours had increased pAKT signalling and were dependent on mammalian target of rapamycin (mTOR). Importantly, in human UCC, there was a significant correlation between high levels of β-catenin and pAKT (and low levels of PTEN). Taken together these data show that deregulated Wnt signalling has a critical role in promoting UCC, and suggests that human UCC that have high levels of Wnt and PI3 kinase signalling may be responsive to mTOR inhibition.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aveyard JS, Skilleter A, Habuchi T, Knowles MA . (1999). Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80: 904–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bienz M, Clevers H . (2000). Linking colorectal cancer to Wnt signaling. Cell 103: 311–320.

    Article  CAS  PubMed  Google Scholar 

  • Bohm M, Kirch H, Otto T, Rubben H, Wieland I . (1997). Deletion analysis at the DEL-27, APC and MTS1 loci in bladder cancer: LOH at the DEL-27 locus on 5p13-12 is a prognostic marker of tumor progression. Int J Cancer 74: 291–295.

    Article  CAS  PubMed  Google Scholar 

  • Burger M, van der Aa MN, van Oers JM, Brinkmann A, van der Kwast TH, Steyerberg EC et al. (2008). Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 54: 835–843.

    Article  PubMed  Google Scholar 

  • Cordon-Cardo C . (2008). Molecular alterations associated with bladder cancer initiation and progression. Scand J Urol Nephrol Suppl 218: 154–165.

    Article  Google Scholar 

  • Cottrell S, Bicknell D, Kaklamanis L, Bodmer WF . (1992). Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 340: 626–630.

    Article  CAS  PubMed  Google Scholar 

  • DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B . (2007). The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 67: 5371–5379.

    Article  CAS  PubMed  Google Scholar 

  • Diaz DS, Segersten U, Malmstrom PU . (2008). Molecular genetics of bladder cancer: an update. Minerva Urol Nefrol 60: 205–216.

    Google Scholar 

  • Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM . (2008). Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci USA 105: 13544–13549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia dMX, Torregrosa A, Munoz J, Castellsague X, Condom E, Vigues F et al. (2000). Prognostic value of the expression of E-cadherin and beta-catenin in bladder cancer. Eur J Cancer 36: 357–362.

    Article  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 

  • He F, Mo L, Zheng XY, Hu C, Lepor H, Lee EY et al. (2009). Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis. Cancer Res 69: 9413–9421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT et al. (1998). Identification of c-MYC as a target of the APC pathway. Science 281: 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  • Howe LR, Brown AM . (2004). Wnt signaling and breast cancer. Cancer Biol Ther 3: 36–41.

    Article  CAS  PubMed  Google Scholar 

  • Ireland H, Kemp R, Houghton C, Howard L, Clarke AR, Sansom OJ et al. (2004). Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology 126: 1236–1246.

    Article  CAS  PubMed  Google Scholar 

  • Kashibuchi K, Tomita K, Schalken JA, Kume H, Yamaguchi T, Muto S et al. (2006). The prognostic value of E-cadherin, alpha-, beta-, and gamma-catenin in urothelial cancer of the upper urinary tract. Eur Urol 49: 839–845.

    Article  CAS  PubMed  Google Scholar 

  • Kastritis E, Murray S, Kyriakou F, Horti M, Tamvakis N, Kavantzas N et al. (2009). Somatic mutations of adenomatous polyposis coli gene and nuclear β-catenin accumulation have prognostic significance in invasive urothelial carcinomas: evidence for Wnt pathway implication. Int J Cancer 124: 103–108.

    Article  CAS  PubMed  Google Scholar 

  • Kemp R, Ireland H, Clayton E, Houghton C, Howard L, Winton DJ . (2004). Elimination of background recombination: somatic induction of Cre by combined transcriptional regulation and hormone binding affinity. Nucleic Acids Res 32: e92.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al. (1991). Identification of FAP locus genes from chromosome 5q21. Science 253: 661–665.

    Article  CAS  PubMed  Google Scholar 

  • Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R et al. (2006). Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 48: 787–794.

    Article  CAS  PubMed  Google Scholar 

  • Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H et al. (2002). Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32: 148–149.

    Article  CAS  PubMed  Google Scholar 

  • Luis NM, Lopez-Knowles E, Real FX . (2007). Molecular biology of bladder cancer. Clin Transl Oncol 9: 5–12.

    Article  CAS  PubMed  Google Scholar 

  • MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ et al. (2007). Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab 6: 329–337.

    Article  CAS  PubMed  Google Scholar 

  • Marsh V, Winton DJ, Williams GT, Dubois N, Trumpp A, Sansom OJ et al. (2008). Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nat Genet 40: 1436–1444.

    Article  CAS  PubMed  Google Scholar 

  • Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR et al. (2005). Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 65: 7081–7085.

    Article  CAS  PubMed  Google Scholar 

  • McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R et al. (2005). Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J 24: 1571–1583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyamoto H, Shuin T, Ikeda I, Hosaka M, Kubota Y . (1996). Loss of heterozygosity at the p53, RB, DCC and APC tumor suppressor gene loci in human bladder cancer. J Urol 155: 1444–1447.

    Article  CAS  PubMed  Google Scholar 

  • Mo L, Cheng J, Lee EY, Sun TT, Wu XR . (2005). Gene deletion in urothelium by specific expression of Cre recombinase. Am J Physiol Renal Physiol 289: F562–F568.

    Article  CAS  PubMed  Google Scholar 

  • Mo L, Zheng X, Huang HY, Shapiro E, Lepor H, Cordon-Cardo C et al. (2007). Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J Clin Invest 117: 314–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moon RT, Kohn AD, De Ferrari GV, Kaykas A . (2004). WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5: 691–701.

    Article  CAS  PubMed  Google Scholar 

  • Nagayama S, Fukukawa C, Katagiri T, Okamoto T, Aoyama T, Oyaizu N et al. (2005). Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene 24: 6201–6212.

    Article  CAS  PubMed  Google Scholar 

  • Nakopoulou L, Zervas A, Gakiopoulou-Givalou H, Constantinides C, Doumanis G, Davaris P et al. (2000). Prognostic value of E-cadherin, beta-catenin, P120ctn in patients with transitional cell bladder cancer. Anticancer Res 20: 4571–4578.

    CAS  PubMed  Google Scholar 

  • Namba R, Young LJ, Abbey CK, Kim L, Damonte P, Borowsky AD et al. (2006). Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ. Clin Cancer Res 12: 2613–2621.

    Article  CAS  PubMed  Google Scholar 

  • Ng SS, Mahmoudi T, Danenberg E, Bejaoui I, de Lau W, Korswagen HC et al. (2009). Phosphatidylinositol 3-kinase signaling does not activate the wnt cascade. J Biol Chem 284: 35308–35313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Novak A, Guo C, Yang W, Nagy A, Lobe CG . (2000). Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28: 147–155.

    Article  CAS  PubMed  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P . (2005). Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108.

    Article  PubMed  Google Scholar 

  • Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR . (2008). Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol Cell Biol 28: 6314–6328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH, Matos T et al. (2009). Inactivation of p53 and Pten promotes invasive bladder cancer. Genes Dev 23: 675–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR et al. (1993). Association of the APC gene product with beta-catenin. Science 262: 1731–1734.

    Article  CAS  PubMed  Google Scholar 

  • Salmena L, Carracedo A, Pandolfi PP . (2008). Tenets of PTEN tumor suppression. Cell 133: 403–414.

    Article  CAS  PubMed  Google Scholar 

  • Schulz WA . (2006). Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119: 1513–1518.

    Article  CAS  PubMed  Google Scholar 

  • Shibata H, Toyama K, Shioya H, Ito M, Hirota M, Hasegawa S et al. (1997). Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278: 120–123.

    Article  CAS  PubMed  Google Scholar 

  • Shiina H, Igawa M, Shigeno K, Terashima M, Deguchi M, Yamanaka M et al. (2002). Beta-catenin mutations correlate with over expression of C-myc and cyclin D1 Genes in bladder cancer. J Urol 168: 2220–2226.

    Article  CAS  PubMed  Google Scholar 

  • Shiina H, Igawa M, Urakami S, Shigeno K, Yoneda T, Terashima M et al. (2001). Alterations of beta- and gamma-catenin in N-butyl-N-(-4-hydroxybutyl) nitrosamine-induced murine bladder cancer. Cancer Res 61: 7101–7109.

    CAS  PubMed  Google Scholar 

  • Shimazui T, Schalken JA, Giroldi LA, Jansen CF, Akaza H, Koiso K et al. (1996). Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res 56: 4154–4158.

    CAS  PubMed  Google Scholar 

  • Stoehr R, Krieg RC, Knuechel R, Hofstaedter F, Pilarsky C, Zaak D et al. (2002). No evidence for involvement of beta-catenin and APC in urothelial carcinomas. Int J Oncol 20: 905–911.

    CAS  PubMed  Google Scholar 

  • Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C et al. (1997). MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57: 5221–5225.

    CAS  PubMed  Google Scholar 

  • Tetsu O, McCormick F . (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426.

    Article  CAS  PubMed  Google Scholar 

  • Tsuruta H, Kishimoto H, Sasaki T, Horie Y, Natsui M, Shibata Y et al. (2006). Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Res 66: 8389–8396.

    Article  CAS  PubMed  Google Scholar 

  • Urakami S, Shiina H, Enokida H, Kawakami T, Kawamoto K, Hirata H et al. (2006a). Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection. Clin Cancer Res 12: 2109–2116.

    Article  CAS  PubMed  Google Scholar 

  • Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T et al. (2006b). Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res 12: 383–391.

    Article  CAS  PubMed  Google Scholar 

  • Wu XR . (2005). Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 5: 713–725.

    Article  CAS  PubMed  Google Scholar 

  • Yoo LI, Liu DW, Le Vu S, Bronson RT, Wu H, Yuan J . (2006). Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner. Cancer Res 66: 1929–1939.

    Article  CAS  PubMed  Google Scholar 

  • You L, He B, Xu Z, Uematsu K, Mazieres J, Fujii N et al. (2004). An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res 64: 5385–5389.

    Article  CAS  PubMed  Google Scholar 

  • Zhang ZT, Pak J, Huang HY, Shapiro E, Sun TT, Pellicer A et al. (2001). Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20: 1973–1980.

    Article  CAS  PubMed  Google Scholar 

  • Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR . (1999). Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res 59: 3512–3517.

    CAS  PubMed  Google Scholar 

  • Zhu X, Kanai Y, Saito A, Kondo Y, Hirohashi S . (2000). Aberrant expression of beta-catenin and mutation of exon 3 of the beta-catenin gene in renal and urothelial carcinomas. Pathol Int 50: 945–952.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by Cancer Research UK and a MRC fellowship to Imran Ahmad and AICR grant to Sorina Radulescu. We thank BICR services, biological services unit, and Colin Nixon and his histology department. We also thank the ‘Think Pink’ charity for the purchase of the Aperio slide scanner and the Slidepath software.

Author information

Authors and Affiliations

  1. The Beatson Institute for Cancer Research, Glasgow, Scotland, UK

    I Ahmad, J P Morton, L B Singh, S M Radulescu, R A Ridgway, H Y Leung & O J Sansom

  2. Centre for Oncology and Applied Pharmacology, University of Glasgow, Glasgow, Scotland, UK

    J P Morton

  3. Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada

    S Patel & J Woodgett

  4. Department of Oncology, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK

    D J Winton

  5. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    M M Taketo

  6. Department of Urology, New York University School of Medicine, New York, NY, USA

    X-R Wu

  7. Department of Pathology, New York University School of Medicine, New York, NY, USA

    X-R Wu

Authors
  1. I Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J P Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L B Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S M Radulescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R A Ridgway
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Woodgett
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D J Winton
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M M Taketo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X-R Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Y Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. O J Sansom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O J Sansom.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmad, I., Morton, J., Singh, L. et al. β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation. Oncogene 30, 178–189 (2011). https://doi.org/10.1038/onc.2010.399

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.399

Keywords

This article is cited by

Search

Advanced search

Quick links