779 Androgen Receptor Phosphorylation is Associated With Clinical Outcome Measures in Hormone Naive Prostate Cancer

Abstract

Introduction: Although prostate cancer (Pca) can be readily diagnosed, estimation of likely outcome remains problematical as many will have a benign course and will not die of their disease, while some patients progress rapidly to castrate resistant disease and die within 18−24 months. Ideally, there would be a factor or factors which would evidently set apart those patients who will, in due course succumb to the disease from those who will not. In Pca activation of signal transduction cascades has been shown to alter androgen receptor (AR) activity. Although it has been suggested that changes in AR phosphorylation might be directly responsible, the candidate kinases mediating phosphorylation is not conclusive. Recent evidence suggests that Protein kinase C (PKC) phosphorylates AR at Serine 578 (pAR). Materials and Methods: The aim of the current study was to investigate if the relationship between the AR and PKC is upheld in clinical prostate cancer specimens. Scansite 2.0 predicted PKC as a strong candidate mediating phosphorylation of AR at serine residue 578. Immunohistochemical analysis was performed to assess protein expression levels of PKC and pAR in a cohort of 90 patients with hormone naive prostate adenocarcinoma. Results and Discussion: High cytoplasmic pAR expression (> median) was significantly associated with time to biochemical relapse (p = 0.034) and with decreased time to death from relapse (p = 0.034). Additionally, high expression of cytoplasmic pAR was significantly associated with decreased disease-specific survival (p = 8.6×10−5), as was high nuclear pAR expression (p = 0.036). Protein expression of PKC was not significantly associated with survival. However, nuclear PKC correlated strongly with pAR expression, in both the cytoplasm (c.c 0.426, p = 0.002) and nucleus (c.c. 0.469, p = 0.001). Conclusion: These results suggest that the phosphorylation of the AR by PKC may be of functional importance in the clinical setting. Consistent with predictions by Scansite expression of PKC significantly correlated with phosphorylation of pAR. Phosphorylation pAR is implicated in Pca progression and survival. Further work investigating the functional consequences of inhibition of AR phosphorylation at serine 578 is warranted.