title: Nuclear iASPP may facilitate prostate cancer progression.
abstract: One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPP(Δ8/Δ8) mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression.
authors.affiliation: 1] Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: E V
authors.initials: EV
authors.lastname: Morris
authors.affiliation: 1] Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: L
authors.initials: L
authors.lastname: Cerundolo
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Cellular Pathology and NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headley Way, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Verrill
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: F
authors.initials: F
authors.lastname: Fritzsche
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: White
authors.affiliation: Department of Urology, Inselspital, Bern, Switzerland.
authors.forename: G N
authors.initials: GN
authors.lastname: Thalmann
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: ten Donkelaar
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: I
authors.initials: I
authors.lastname: Ratnayaka
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: V
authors.initials: V
authors.lastname: Salter
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: F C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: 1] Ludwig Institute for Cancer Research Ltd, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK [2] Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building (off Roosevelt Drive), Headington, Oxford, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bryant
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D018920:Coculture Techniques; D015331:Cohort Studies; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011379:Prognosis; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery; D012097:Repressor Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C119612:PPP1R13L protein, human; C501916:Ppp1r13l protein, mouse; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins