title: β-Catenin activation synergizes with PTEN loss to cause bladder cancer formation.
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-catenin(exon3/+)). 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.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, Scotland, UK.
authors.forename: I
authors.initials: I
authors.lastname: Ahmad
authors.forename: J P
authors.initials: JP
authors.lastname: Morton
authors.forename: L B
authors.initials: LB
authors.lastname: Singh
authors.forename: S M
authors.initials: SM
authors.lastname: Radulescu
authors.forename: R A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: J
authors.initials: J
authors.lastname: Woodgett
authors.forename: D J
authors.initials: DJ
authors.lastname: Winton
authors.forename: M M
authors.initials: MM
authors.lastname: Taketo
authors.forename: X-R
authors.initials: XR
authors.lastname: Wu
authors.forename: H Y
authors.initials: HY
authors.lastname: Leung
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002291:Carcinoma, Papillary / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism; D017384:Sequence Deletion; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*; D019459:Urothelium / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins; D051176:beta Catenin; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C487757:Pten protein, mouse
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2109-16
references.pmid: 16609023
references.citation: Int J Oncol. 2002 May;20(5):905-11
references.pmid: 11956582
references.citation: Cell. 2000 Oct 13;103(2):311-20
references.pmid: 11057903
references.citation: Cancer Res. 1999 Jul 15;59(14):3512-7
references.pmid: 10416618
references.citation: J Urol. 2002 Nov;168(5):2220-6
references.pmid: 12394763
references.citation: Nature. 1999 Apr 1;398(6726):422-6
references.pmid: 10201372
references.citation: Science. 1997 Oct 3;278(5335):120-3
references.pmid: 9311916
references.citation: Cancer Res. 2009 Dec 15;69(24):9413-21
references.pmid: 19951992
references.citation: Nat Genet. 2008 Dec;40(12):1436-44
references.pmid: 19011632
references.citation: J Clin Invest. 2007 Feb;117(2):314-25
references.pmid: 17256055
references.citation: Cancer Res. 1996 Sep 15;56(18):4154-8
references.pmid: 8797585
references.citation: Cancer Res. 2001 Oct 1;61(19):7101-9
references.pmid: 11585741
references.citation: Cancer Res. 2005 Aug 15;65(16):7081-5
references.pmid: 16103055
references.citation: Clin Cancer Res. 2006 Apr 15;12(8):2613-21
references.pmid: 16638874
references.citation: J Biol Chem. 2009 Dec 18;284(51):35308-13
references.pmid: 19850932
references.citation: Nucleic Acids Res. 2004 Jul 01;32(11):e92
references.pmid: 15247325
references.citation: Nat Rev Genet. 2004 Sep;5(9):691-701
references.pmid: 15372092
references.citation: Cancer Res. 2007 Jun 1;67(11):5371-9
references.pmid: 17545618
references.citation: Br J Cancer. 1999 May;80(5-6):904-8
references.pmid: 10360673
references.citation: Eur Urol. 2008 Oct;54(4):835-43
references.pmid: 18166262
references.citation: Am J Physiol Renal Physiol. 2005 Sep;289(3):F562-8
references.pmid: 15840768
references.citation: Histopathology. 2006 Jun;48(7):787-94
references.pmid: 16722926
references.citation: Int J Cancer. 1997 Jun 20;74(3):291-5
references.pmid: 9221807
references.citation: Clin Transl Oncol. 2007 Jan;9(1):5-12
references.pmid: 17272224
references.citation: Cell Metab. 2007 Oct;6(4):329-37
references.pmid: 17908561
references.citation: Nat Rev Cancer. 2005 Sep;5(9):713-25
references.pmid: 16110317
references.citation: Gastroenterology. 2004 May;126(5):1236-46
references.pmid: 15131783
references.citation: Cancer Res. 2006 Feb 15;66(4):1929-39
references.pmid: 16488991
references.citation: Cell. 2008 May 2;133(3):403-14
references.pmid: 18455982
references.citation: Cancer Biol Ther. 2004 Jan;3(1):36-41
references.pmid: 14739782
references.citation: Science. 1993 Dec 10;262(5140):1731-4
references.pmid: 8259518
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):383-91
references.pmid: 16428476
references.citation: Eur Urol. 2006 May;49(5):839-45; discussion 845
references.pmid: 16426728
references.citation: Genesis. 2000 Nov-Dec;28(3-4):147-55
references.pmid: 11105057
references.citation: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references.pmid: 15761078
references.citation: Mol Cell Biol. 2008 Oct;28(20):6314-28
references.pmid: 18694957
references.citation: Eur J Cancer. 2000 Feb;36(3):357-62
references.pmid: 10708937
references.citation: Pathol Int. 2000 Dec;50(12):945-52
references.pmid: 11123760
references.citation: EMBO J. 2005 Apr 20;24(8):1571-83
references.pmid: 15791206
references.citation: Minerva Urol Nefrol. 2008 Dec;60(4):205-16
references.pmid: 18923358
references.citation: Genesis. 2002 Feb;32(2):148-9
references.pmid: 11857804
references.citation: Scand J Urol Nephrol Suppl. 2008 Sep;(218):154-65
references.pmid: 18815930
references.citation: Genes Dev. 2000 Aug 1;14(15):1837-51
references.pmid: 10921899
references.citation: EMBO J. 1999 Nov 1;18(21):5931-42
references.pmid: 10545105
references.citation: Cancer Res. 2006 Sep 1;66(17):8389-96
references.pmid: 16951148
references.citation: Int J Cancer. 2009 Jan 1;124(1):103-8
references.pmid: 18844223
references.citation: Oncogene. 2001 Apr 12;20(16):1973-80
references.pmid: 11360181
references.citation: Genes Dev. 2009 Mar 15;23(6):675-80
references.pmid: 19261747
references.citation: Anticancer Res. 2000 Nov-Dec;20(6B):4571-8
references.pmid: 11205306
references.citation: Int J Cancer. 2006 Oct 1;119(7):1513-8
references.pmid: 16557569
references.citation: J Urol. 1996 Apr;155(4):1444-7
references.pmid: 8632608
references.citation: Cancer Res. 1997 Dec 1;57(23):5221-5
references.pmid: 9393738
references.citation: Science. 1998 Sep 4;281(5382):1509-12
references.pmid: 9727977
references.citation: Science. 1991 Aug 9;253(5020):661-5
references.pmid: 1651562
references.citation: Lancet. 1992 Sep 12;340(8820):626-30
references.pmid: 1355210