Abstract A11: Categorization of castration-resistant prostate cancer bone metastases according to expression of steroid-converting enzymes and constitutively active androgen receptor variants

Abstract

Abstract Patients with advanced prostate cancer (PC) are given androgen ablation therapy. After a period of initial remission tumors eventually relapse, predominantly within the bone, and are then termed castration-resistant prostate cancer (CRPC). The majority of CRPC tumors express the androgen receptor (AR) and AR regulated genes. Possible mechanisms behind AR activity in CRPC include steroid synthesis by tumor cells and expression of constitutively active AR variants. We have previously found high levels of cholesterol in prostate cancer bone metastases that theoretically could be the substrate for CYP11 and intra-tumoral synthesis of steroids (Thysell et al, 2010). Steroid-converting enzymes have, as far as we know, not been thoroughly examined in PC bone metastases, and the aim of this study was therefore to analyze the expression of the main enzymes involved in the conversion of cholesterol into testosterone (T) and dihydrotestosterone (DHT) in hormone-naïve (HN) and CRPC bone metastases in comparison to primary tumors. We have previously also shown that the constitutively active AR variant AR-V7 is expressed at high levels in CRPC bone metastases in patients with particularly poor prognosis (Hörnberg et al, 2011). Another aim of this study was therefore to evaluate if CRPC bone metastases could be differentiated according to expression of steroid-converting enzymes and AR-V7 into sub-groups with potentially different mechanisms behind castration-resistance. Expression levels of the enzymes included in the classical and backdoor steroidogenesis pathways were analyzed by applying an Illumina whole-genome array to total RNA extracted from frozen biopsies of prostate tissue obtained at radical prostatectomy and metastasis surgery, respectively. Levels were compared between HN bone metastases (n=10), CRPC bone metastases (n=30), and non-malignant (n=12) and malignant (n=13) areas of the primary tumors. Results were verified using RT-PCR and immunohistochemistry in an extended series of samples. Significant increased gene expression levels of HSD17B10 were found in CRPC compared to HN bone metastases, which possibly indicated enhanced conversion of androstanediol to DHT in CRPC metastases. The CRPC metastases did however not show higher levels of CYP11, CYP17, AKR1C3, HSD3B2, or SRD5A1/2 than the HN metastases, indicating no general induction of the classical steroidogenesis pathway in CRPC bone metastases. The expression levels of AKR1C3 and AKR1C2 were significantly higher, and of SRD5A2 significantly lower, in bone metastases than in primary tumors, with highly variable levels found for AKR1C3. About 20% of the CRPC metastases expressed extremely high levels of AKR1C3 which suggested the likelihood of androstenedione conversion into T in those tumors. Another 20% of the CRPC metastases expressed extreme values of the constitutively active AR-V7. In conclusion, AKR1C3 and AR-V7 expression in bone metastases were able to categorize CRPC patients according to potentially different mechanisms behind castration-resistance, and may furthermore also influence patient response to different types of anti-androgen therapies. Citation Format: Emma Jernberg, Anders Widmark, Sead Crnalic, Anders Bergh, Pernilla Wikström. Categorization of castration-resistant prostate cancer bone metastases according to expression of steroid-converting enzymes and constitutively active androgen receptor variants [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A11.