The Prognostic Significance of Androgen Receptor Phosphorylation in Prostate Cancer


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Si Jie Heng1,Claire Tannahill1,Claire Adams1,Pamela McCall1,Morag Seywright2,Mark Underwood3,Joanne Edwards1
1University of Glasgow, Glasgow, United Kingdom,2Western Infirmary, Glasgow, United Kingdom,3Glasgow Royal Infirmary, Glasgow, United Kingdom

Background

Alterations in androgen receptor (AR) phosphorylation may contribute to prostate cancer development and progression given the functional importance of AR phosphorylation and the AR-dependence of most prostate cancers. Cdk1 is postulated to phosphorylate multiple serine sites, including Ser-81, on the AR. This study aims to investigate Cdk1-mediated phosphorylation of the AR and its significance in prostate cancer in the clinical setting.

Method

92 patients with biopsy samples available at diagnosis of prostatic adenocarcinoma and clinical follow-up were retrospectively selected for analysis. Scansite 2.0 was utilized to predict Cdk1 target sites on the AR, which included Ser-81, Ser-94, Ser-210, Ser-308, Ser-515, Ser-650 and Ser-790. Immunohistochemistry (IHC) was performed on biopsy samples to stain for expression of Cdk1, AR and AR phosphorylated at the serine residues mentioned above. IHC staining intensity was quantified using the weighted histo-score method by 2 independent observers blinded to clinical outcomes.

Results

Cdk1 expression correlated with phosphorylation of all predicted sites in at least one cellular location. High expression of cytoplasmic Cdk1, AR and phosho-AR515 (pAR515) were associated with both decreased disease-specific (p=0.002, p=0.010, p=0.001 respectively) and overall survival (p=0.005, p=0.014, p=0.003 respectively). However, only high expression of pAR515 was associated with disease-specific survival on multivariate analysis.  In a Cox-regression model, high cytoplasmic pAR515 expression (p=0.004), and high Gleason score (p=3.9 x 10-4) were each independently associated with decreased disease-specific survival.

Conclusion

Our results support the phosphorylation of multiple serine sites on the AR by Cdk1 in the clinical setting.  High expression of Cdk1 and phosphorylation of a few specific serine residues on the AR are associated with disease-specific and overall survival. Ser-515 phosphorylation by Cdk1 may have a critical role in the development and progression of prostate cancer. Most importantly, pAR515 may act as a useful prognostic biomarker in prostate cancer at diagnosis.