Androgen Receptor Phosphorylation at Serine 308 and Serine 791 Predicts Enhanced Survival in Castrate Resistant Prostate Cancer Patients

Pamela Mccall,Mark Underwood,Claire Adams,Lindsay Bennett,Tahir Qayyum,Jennifer Willder,Joanne Edwards,Clare Orange

doi:10.3390/ijms140816656

Abstract

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR94), 308 (pAR308), 650(pAR650) and 791 (pAR791). No correlations with clinical parameters were observed for pAR94 or pAR650 in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR308 is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR791 expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer.

Highlights

Prostate cancer has the highest cancer incidence in males and is the second highest cause of male cancer related mortality [1]
We have previously reported that the expression and activation of the PI3K/Akt cascade influences the progression to castrate resistant disease using clinical prostate cancer tumours, where phosphorylation of androgen receptor (AR) at the Akt consensus site serine 213 was significantly associated with disease progression [14,15]
The aim of the current study was to establish if other AR phosphorylation sites are associated with patient survival and determine if inhibition or activation at these phosphorylation sites could be employed as therapeutic targets

Summary

Introduction

Prostate cancer has the highest cancer incidence in males and is the second highest cause of male cancer related mortality [1]. Current clinical data implies that the AR is expressed and continues to mediate androgen signalling after failure of this therapeutic approach As this does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumour cells to maintain AR signalling, especially in the context of up-regulated receptor levels or increased sensitivity of the AR for activation. Ligands of non-testicular origin (adrenal gland or the tumour cells themselves) or ligand-independent activation can contribute to continued AR signalling. To overcome this and to improve patient treatment options, the mechanisms underlying the development of castrate resistance must be fully understood

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