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Abstract
PurposeProstate 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.MethodsImmunohistochemistry 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.ResultsNuclear 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)ConclusionspARS578 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.
Highlights
Over the last 10 years we have observed increasing incidence and decreasing mortality trends in prostate cancer
Conclusions: pARS578 expression is associated with poor outcome and is a potential independent prognostic marker in hormone-naïve prostate cancer
Forty-six died from prostate cancer and twenty deaths were attributed to inter-current disease
Summary
Over the last 10 years we have observed increasing incidence and decreasing mortality trends in prostate cancer. Incidence-mortality ratios were approximately 2:1 in Western Europe prior to the introduction of PSA testing. This ratio has increased to over 7:1, illustrating the level of over-diagnosis [1]. Many patients have indolent tumours that, before PSA testing, would not have been clinically apparent in their lifetime. The diagnosis, treatment and 5 year follow-up cost of prostate cancer in the UK was estimated at £136, 278, 237 in 2010 [2]. The main challenge for prostate cancer research and clinical care is the quandary of how to continue driving mortality rates downward while minimising over-treatment
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