title: Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.
abstract: Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom; imran.ahmad@glasgow.ac.uk h.leung@beatson.gla.ac.uk.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Laura
authors.initials: L
authors.lastname: Galbraith
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Rachana
authors.initials: R
authors.lastname: Patel
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Ee Hong
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Salji
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Peter
authors.initials: P
authors.lastname: Repiscak
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Ann
authors.initials: A
authors.lastname: Hedley
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Elke
authors.initials: E
authors.lastname: Markert
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Carolyn
authors.initials: C
authors.lastname: Loveridge
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom;
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, United Kingdom; imran.ahmad@glasgow.ac.uk h.leung@beatson.gla.ac.uk.
authors.forename: Hing Y
authors.initials: HY
authors.lastname: Leung
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019895:Transposases
chemical_list: D047495:PPAR gamma; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019895:Transposases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: PPARG; PTEN; Sleeping Beauty; metastasis; prostate cancer