title: The role of c-Jun and c-Fos expression in androgen-independent prostate cancer.
abstract: Molecular mechanisms underlying the development of androgen-insensitive prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. Cell line studies demonstrate that c-Jun and c-Fos, via formation of the transcription factor activated protein 1 (AP-1), activate androgen-regulated genes independent of androgens and that c-Jun alone acts as an androgen receptor co-factor. The aim of this study was to investigate whether increased levels of c-Jun and phosphorylated c-Jun are associated with the development of AIPC using clinical material. Material from a cohort of 51 patients with paired tumours, obtained before and after the development of AIPC, and with full clinical biochemical follow-up, was retrieved from the archives. Tumour c-Jun, activated c-Jun, c-Fos, and pan protein kinase C (PKC) protein expression were analysed by immunohistochemistry and protein expression was scored by two independent observers using a weighted histoscore. No evidence was found to suggest that c-Jun acting as an androgen receptor co-factor influences the development of AIPC. However, it was observed that patients with high expression levels of phosphorylated c-Jun had a significantly shorter survival from relapse compared with patients with low phosphorylated c-Jun protein expression (p = 0.023), suggesting that increased AP-1 levels may promote AIPC tumour growth. Whilst PKC did not appear to activate c-Jun in vivo, increased PKC expression in AIPC tumours was also associated with decreased patient survival from time of relapse (p = 0.014). In conclusion, the data support the hypothesis that activation of c-Jun plays a role in the development of AIPC via AP-1 formation in some patients. However, PKC appears to promote the development of AIPC independently of c-Jun activation via an as yet unexplained mechanism.
authors.affiliation: Endocrine Cancer Group, Section of Surgical and Translational Research, University of Glasgow, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK. jel0b@clinmed.gla.ac.uk
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.forename: N Sarath
authors.initials: NS
authors.lastname: Krishna
authors.forename: Rono
authors.initials: R
authors.lastname: Mukherjee
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D000368:Aged; D000728:Androgens / Q000502:physiology*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis*; D009364:Neoplasm Recurrence, Local; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000503:physiopathology; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis*; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis*; D012189:Retrospective Studies; D016019:Survival Analysis; D018808:Transcription Factor AP-1 / Q000032:analysis
chemical_list: D000728:Androgens; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D011493:Protein Kinase C