Androgen receptor phosphorylation status at serine 578 predicts poor outcome in prostate cancer patients.

Prostate cancer growth is dependent upon androgen receptor (AR) activation, regulated via phosphorylation. Protein kinase C (PKC) is one kinase that can mediate AR phosphorylation. This study aimed to establish if AR phosphorylation by PKC is of prognostic significance.

Immunohistochemistry for AR, AR phosphorylated at Ser-81 (pARS81), AR phosphorylated at Ser-578 (pARS578), PKC and phosphorylated PKC (pPKC) was performed on 90 hormone-naïve prostate cancer specimens. Protein expression was quantified using the weighted histoscore method and examined with regard to clinico-pathological factors and outcome measures; time to biochemical relapse, survival from biochemical relapse and disease-specific survival.

Nuclear PKC expression strongly correlated with nuclear pARS578 (c.c. 0.469, p=0.001) and cytoplasmic pARS578 (c.c. 0.426 p=0.002). High cytoplasmic and nuclear pARS578 were associated with disease-specific survival (p<0.001 and p=0.036 respectively). High nuclear PKC was associated with lower disease-specific survival when combined with high pARS578 in the cytoplasm (p=0.001) and nucleus (p=0.038). Combined high total pARS81 and total pARS578 was associated with decreased disease-specific survival (p=0.005)Conclusions: pARS578 expression is associated with poor outcome and is a potential independent prognostic marker in hormone-naïve prostate cancer. Furthermore, PKC driven AR phosphorylation may promote prostate cancer progression and provide a novel therapeutic target.

Oncotarget. 2016 Jan 25 [Epub ahead of print]

Patek Sc, Willder Jm, Heng Js, Taylor B, Horgan Pg, Leung Hy, Underwood Ma, Edwards J

Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow G12 8QQ, UK., Academic Department of Surgery, School of Medicine, University of Glasgow, Walton Building, Glasgow Royal Infirmary, Glasgow, G4 0SF, UK., Department of Urology, Queen Elizabeth University Hospital, Glasgow G31 2ER, UK.