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THE ROLE OF THE PI3K/AKT CASCADE IN HORMONE REFRACTORY PROSTATE CANCER J Edwards*, P Traynor, L Tam, A. F. Munro, J.M.S. Bartlett [email protected] Endocrine Cancer Group, Section of Surgical and Translational Sciences, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, UK INTRODUCTION. Prostate cancer is the second most common male malignancy in the western world. Treatment of advanced prostate cancer relies on androgen deprivation. Although the majority of patients initially respond to androgen deprivation therapy, the mean time to relapse is 12-18 months. Recently, major advances have been made in understanding post-translational modifications to the androgen receptor (AR). Phosphorylation of AR, in vitro, via the PI3K/Akt signal transduction pathways, has been shown to activate the AR and sensitise it to low circulating levels of androgens (1). We recently reported that genes for members of the PI3K/Akt pathway are more commonly amplified in hormone refractory tumours compared to matched hormone sensitive tumours (2). Here we tested the functional significance of these modifications in the development of hormone refractory prostate cancer. METHODS. AR protein expression, AR phosphorylation at the Akt consensus site Serine 210 (phospho AR) and phosphorylated Akt (at both the Theronine 308 and Serine 473 phosphorylation sites) was determined by immunohistochemistry in a cohort of matched tumour pairs (one taken before and one after hormone relapse) from 53 prostate cancer patients. Detection and visualisation was achieved using the LSAB+ kit (DAKO Cytomation) for AR and phospho AR) or EnVision (DAKO Cytomation) (phospho Akt) and DAB kit (Vector Laboratories). Two independent observers using a weighted histoscore method scored each section. RESULTS. AR expression levels were significantly higher in hormone resistant tumours compared to matched hormone sensitive tumours from the same patient, (130 (55-167) vs 94.5 (55-120) p=0.019), AR expression was not associated with patient survival (3). Phospho AR expression was also significantly higher in hormone resistant tumours compared to matched hormone sensitive tumours (107.5(57.5-175.5) vs 50(0-92) p=0.0005). Further, patient phospho AR expression above the median value in hormone refractory tumours had significantly shorter survival from time of biochemical relapse than patients with low (below the median) phospho AR expression (p=0.0076), this was also observed for shorter overall survival (p=0.034). Almost half the patients in this study showed a marked increase in phospho AR expression with the development of hormone refractory disease (47%, 25/53). In these patients a significant reduction in time to death from biochemical relapse (p=0.0004) and overall survival (p=0.023) was observed relative to patients who had a decrease in phospho AR expression (8%, 4/53) or no change in phospho AR expression (45%, 24/53). Protein expression of phospho AR was not linked with expression of HER2, pHER2, EGFR, and pEGFR; up stream regulators of the PI3K cascade. However membrane expression of Akt phosphorylated at serine 473, does positively correlate with phospho AR expression (p=0.049). CONCLUSION. Activation of AR by phosphorylation at the Akt consensus site (Serine 210) is significantly increased with the development of hormone refractory prostate cancer and high expression of phospho AR is associated with significantly reduced patient survival. Akt activation is linked to AR activation suggesting that inhibition of the PI3K/Akt cascade, to inhibit AR phosphorylation could be a novel therapeutic target for treatment of hormone refractory prostate cancer. ACKNOWLEDGMENT. This work was supported by TENOVUS Scotland and theProstate Cancer Charitable Trust. REFERENCES 1. Ghosh P.M., Malik S., Bedolla R., Kreisberg J.I. (2003) Current Drug Metabolism 4 487-496 2. Edwards J., Krishna N.S., Witton C..J, Bartlett J.M.S. (2003). Clin. Cancer Res. 9, 5271-5281. 3. Edwards J., Krishna N.S., Bartlett J.M.S. (2003). Brit J. Cancer 198, 237-244