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- W2752853570 abstract "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/flK-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." @default.
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- W2752853570 date "2017-11-14" @default.
- W2752853570 modified "2023-10-15" @default.
- W2752853570 title "PTEN loss and activation of K-RAS and β-catenin cooperate to accelerate prostate tumourigenesis" @default.
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- W2752853570 cites W1971727526 @default.
- W2752853570 cites W1980432649 @default.
- W2752853570 cites W1982395176 @default.
- W2752853570 cites W1984407262 @default.
- W2752853570 cites W1991560250 @default.
- W2752853570 cites W1995496043 @default.
- W2752853570 cites W1998203489 @default.
- W2752853570 cites W2002702229 @default.
- W2752853570 cites W2009302881 @default.
- W2752853570 cites W2011957420 @default.
- W2752853570 cites W2017294712 @default.
- W2752853570 cites W2018553282 @default.
- W2752853570 cites W2019041110 @default.
- W2752853570 cites W2019686202 @default.
- W2752853570 cites W2024732985 @default.
- W2752853570 cites W2029318868 @default.
- W2752853570 cites W2036609075 @default.
- W2752853570 cites W2043144737 @default.
- W2752853570 cites W2046234516 @default.
- W2752853570 cites W2051025382 @default.
- W2752853570 cites W2056846905 @default.
- W2752853570 cites W2058138221 @default.
- W2752853570 cites W2062289724 @default.
- W2752853570 cites W2067602854 @default.
- W2752853570 cites W2070829001 @default.
- W2752853570 cites W2070998226 @default.
- W2752853570 cites W2071665742 @default.
- W2752853570 cites W2073100248 @default.
- W2752853570 cites W2076892771 @default.
- W2752853570 cites W2077297619 @default.
- W2752853570 cites W2085950149 @default.
- W2752853570 cites W2086382688 @default.
- W2752853570 cites W2087999409 @default.
- W2752853570 cites W2090583090 @default.
- W2752853570 cites W2090652850 @default.
- W2752853570 cites W2090756832 @default.
- W2752853570 cites W2090863421 @default.
- W2752853570 cites W2094349651 @default.
- W2752853570 cites W2094941511 @default.
- W2752853570 cites W2102629949 @default.
- W2752853570 cites W2107275684 @default.
- W2752853570 cites W2107633226 @default.
- W2752853570 cites W2108420484 @default.
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- W2752853570 cites W2118252933 @default.
- W2752853570 cites W2118677643 @default.
- W2752853570 cites W2121158863 @default.
- W2752853570 cites W2125819870 @default.
- W2752853570 cites W2130875528 @default.
- W2752853570 cites W2132790996 @default.
- W2752853570 cites W2134359750 @default.
- W2752853570 cites W2134757689 @default.
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- W2752853570 cites W2150701033 @default.
- W2752853570 cites W2159715390 @default.
- W2752853570 cites W2162744380 @default.
- W2752853570 cites W2164895949 @default.
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- W2752853570 doi "https://doi.org/10.1002/path.4977" @default.
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