title: Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model.
abstract: Multiple genetic alterations are associated with prostate carcinogenesis. Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Previous studies showed that EAF2 knockout caused tumors in multiple organs and prostatic intraepithelial neoplasia (PIN) in mice. However, EAF2-knockout mice did not develop prostate cancer even at 2 years of age. To further define the roles of EAF2 in prostate carcinogenesis, we crossed the Pten+/- and EAF2+/- mice in the C57/BL6 background to generate EAF2-/-Pten+/-, Pten+/-, EAF2-/- and wild-type mice. The prostates from virgin male mice with the above four genotypes were analyzed at 7 weeks, 19 weeks and 12 months of age. Concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2-/- Pten+/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2-/-Pten+/- mice. Using laser-capture microdissection coupled with real-time reverse transcription-PCR, we confirmed that co-downregulation of EAF2 and Pten occurred in >50% clinical prostate cancer specimens with Gleason scores of 8-9 (n=11), which is associated with poor prognosis. The above findings together demonstrated synergistic functional interactions and clinical relevance of concurrent EAF2 and Pten downregulation in prostate carcinogenesis.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ai
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Pascal
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Malley
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Dar
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Isharwal
authors.affiliation: Department of Urology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ren
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Rigatti
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dhir
authors.affiliation: Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Nelson
authors.affiliation: 1] Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [3] University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000483:Alleles; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D061346:Laser Capture Microdissection; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055806:Microvessels / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011467:Prostate / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C483108:FESTA protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse