Dataset Information

?-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 ?-catenin to the urothelium of transgenic mice using Cre-Lox technology (UroIICRE(+) ?-catenin(exon3/+)). Expression of this activated form of ?-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 ?-catenin and PTEN expression. This PTEN expression blocked proliferation. Next, we combined PTEN deficiency with ?-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 ?-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.

SUBMITTER: Ahmad I

PROVIDER: S-EPMC3044461 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ahmad I I Morton J P JP Singh L B LB Radulescu S M SM Ridgway R A RA Patel S S Woodgett J J Winton D J DJ Taketo M M MM Wu X-R XR Leung H Y HY Sansom O J OJ

Oncogene 20100906 2

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 lesio ...[more]

PMID: 20818428

Similar Datasets

Project description:Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Ptenfl/fl ), to activate the PI3K signalling pathway, with either dominant stabilized β-catenin [Catnb+/lox(ex3) ] or activated K-RAS (K-Ras+/V12 ) to aberrantly activate WNT and MAPK signalling, respectively. Synchronous activation of all three pathways (triple mutants) significantly reduced survival (median 96 days) as compared with double mutants [median: 140 days for Catnb+/lox(ex3) Ptenfl/fl ; 182 days for Catnb+/lox(ex3) K-Ras+/V12 ; 238 days for Ptenfl/fl K-Ras+/V12 ], and single mutants [median: 383 days for Catnb+/lox(ex3) ; 407 days for Ptenfl/fl ], reflecting the accelerated tumourigenesis. Tumours followed a stepwise progression from mouse prostate intraepithelial neoplasia to invasive adenocarcinoma, similar to that seen in human disease. There was significantly elevated cellular proliferation, tumour growth and percentage of invasive adenocarcinoma in triple mutants as compared with double mutants and single mutants. Triple mutants showed not only activated AKT, extracellular-signal regulated kinase 1/2, and nuclear β-catenin, but also significantly elevated signalling through mechanistic target of rapamycin complex 1 (mTORC1). In summary, we show that combined deregulation of the PI3K, MAPK and WNT signalling pathways drives rapid progression of prostate tumourigenesis, and that deregulation of all three pathways results in tumours showing aberrant mTORC1 signalling. As mTORC1 signalling is emerging as a key driver of androgen deprivation therapy resistance, our findings are important for understanding the biology of therapy-resistant prostate cancer and identifying potential approaches to overcome this. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets