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

PURPOSE: 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. METHODS: Immunohistochemistry for AR, AR phosphorylated at Ser-81 (pAR(S81)), AR phosphorylated at Ser-578 (pAR(S578)), 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. RESULTS: Nuclear PKC expression strongly correlated with nuclear pAR(S578) (c.c. 0.469, p=0.001) and cytoplasmic pAR(S578) (c.c. 0.426 p=0.002). High cytoplasmic and nuclear pAR(S578) 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 pAR(S578) in the cytoplasm (p=0.001) and nucleus (p=0.038). Combined high total pAR(S81) and total pAR(S578) was associated with decreased disease-specific survival (p=0.005) CONCLUSIONS: pAR(S578) 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.