Androgen Receptor Phosphorylation Is Associated With Clinical Outcome Measures In Castrate Resistant Prostate Cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Androgen Receptor phosphorylation is associated with clinical outcome measures in castrate resistant prostate cancer. Pamela McCall, Claire Adams, Yinrue Lim, Morag Sewright, Clare Orange and Joanne Edwards. Prostate cancer has high cancer incidence in males and is the second highest cause of male cancer related mortality. Alterations in androgen receptor (AR) phosphorylation may contribute to prostate cancer development and progression. Investigating the phosphorylation status of the AR in clinical samples will further our understanding of the mechanisms underlying the development of castrate resistant prostate cancer (CRPC) and possibly identify innovative therapeutic targets and prognostic markers. We reported expression of AR phosphorylated at serine 213 (ARs213) was associated with poor prognosis in CRPC patients (McCall et al, BJC 2008). We have extended this patient cohort and investigated which other AR phosphorylation sites are related to progression to CRPC. Immunohistochemical analysis was performed to assess expression levels of AR, ARs81, ARs94, ARs213, ARs308, ARs650 and ARs791 in a cohort of 84 prostate cancer patients. In CRPC high expression of AR and ARs213 was associated of presence of metastases at relapse (p=0.018 and p=0.046, respectively) and with decreased time to death from relapse (p=0.038 and p=0.003). ARs213 is also associated with a decreased overall disease specific survival (p=0.008). In contrast low expression of ARs791 was associated with decreased time to death from relapse (p=0.04) and low expression of ARs308 was associated with decreased disease specific survival (p=0.011). Use of paired tumours from each patient allowed changes in protein expression in the transition from hormone naive to castrate resistant disease to be assessed. Total AR, ARs213 and ARs650 increased with the development of CRPC (p<0.001, p<0.001 and p=0.003 respectively) and ARs81 decreased with the development of CRPC (p=0.001). Akt is postulated to phosphorylate serine sites s213 and s791 on AR. As phosphorylation of the AR at these residues appear to be involved in prostate cancer progression inhibition of PI3K by P85 siRNA treatment was analysed. PI3K specific siRNA treatment decreased the expression of Akts473, ARs213 and ARs791, as expected silencing PI3K has no apparent effect on AR or ARs81 expression. Whether targeted inhibition of AR phosphorylation through PI3K siRNA inhibits prostate cancer cell growth and metastasis in vitro remains to be elucidated. In vitro results suggest that phosphorylation at ARs213 sensitises the AR to low levels of androgens and allow prostate cancer growth in low androgen conditions. Therefore ARs213 may serve as a diagnostic tool to predict patient outcome in response to hormone deprivation therapy and inhibition of ARs213 via the PI3K pathway may be an effective therapeutic avenue to investigate for treatment of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-325. doi:10.1158/1538-7445.AM2011-LB-325