title: Expression of E6AP and PML predicts for prostate cancer progression and cancer-specific death.
abstract: BACKGROUND
  The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown.
  
  
  METHODS
  E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data.
  
  
  RESULTS
  Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence.
  
  
  CONCLUSIONS
  This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.
authors.affiliation: Department of Pathology, Peter MacCallum Cancer, East Melbourne. Electronic address: simonebirch@mac.com.
authors.forename: S E
authors.initials: SE
authors.lastname: Birch
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney; Sydney Medical School, University of Sydney, Sydney; The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney.
authors.forename: J G
authors.initials: JG
authors.lastname: Kench
authors.affiliation: Department of Pathology, Peter MacCallum Cancer, East Melbourne.
authors.forename: E
authors.initials: E
authors.lastname: Takano
authors.affiliation: Department of Pathology, Peter MacCallum Cancer, East Melbourne.
authors.forename: P
authors.initials: P
authors.lastname: Chan
authors.affiliation: Department of Pathology, University of Melbourne, Melbourne.
authors.forename: A-L
authors.initials: AL
authors.lastname: Chan
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney.
authors.forename: K
authors.initials: K
authors.lastname: Chiam
authors.affiliation: NHMRC Clinical Trial Centre, University of Sydney, Sydney.
authors.forename: A-S
authors.initials: AS
authors.lastname: Veillard
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney; Department of Urology, St Vincent's Clinic, Sydney.
authors.forename: P
authors.initials: P
authors.lastname: Stricker
authors.affiliation: Department of Pathology, University of Melbourne, Melbourne.
authors.forename: S
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Department of Pathology, Peter MacCallum Cancer, East Melbourne; Department of Pathology, University of Melbourne, Melbourne; Department of Biochemistry and Molecular Biology, Monash University, Melbourne.
authors.forename: Y
authors.initials: Y
authors.lastname: Haupt
authors.affiliation: Sydney Medical School, University of Sydney, Sydney; The Kinghorn Cancer Centre, Garvan Institute for Medical Research, Sydney; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Horvath
authors.affiliation: Department of Pathology, Peter MacCallum Cancer, East Melbourne; Department of Pathology, University of Melbourne, Melbourne; Department of Pathology, University of Melbourne, Melbourne.
authors.forename: S B
authors.initials: SB
authors.lastname: Fox
mesh_terms: D015331:Cohort Studies; D018450:Disease Progression; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases
keywords: E6AP; PML; cancer recurrence; prognostic marker; prostate cancer