207 POLYMORPHISMS IN CYP17A1, CYP3A4 AND CYP3A43 GENES INVOLVED ANDROGEN PATHWAYS AS RISK FACTORS FOR PROSTATE CANCER IN KOREAN POPULATION

Vol. 189, No. 4S, Supplement, Sunday, May 5, 2013

ERG in GP3/4/5 of PT and MET were: 38%/37%/24% and 23%/30%/ 39%. Concordance in TMPRSS2-ERG status between PT and MET was relatively poor (Kappa 0.39) showing 21% and 8% of cancers with gene fusion solely in the PT and MET, respectively. TMPRSS2-ERG fusion was not correlated with specific tumor features and predicted late tumor recurrence independently when present in PT (HR 0.65; p⫽0.041). CONCLUSIONS: In PT TMPRSS2-ERG fusion is more frequent and its distribution more heterogeneous as compared to MET. The gene fusion in primary tumors independently predicts late biochemical recurrence. Source of Funding: None

206 HIGH MOBILITY GROUP PROTEIN AT-HOOK 1 (HMGA1) IS ASSOCIATED WITH THE DEVELOPMENT OF ANDROGEN INDEPENDENCE AND DOCETAXEL-RESISTANCE IN PROSTATE CANCER CELLS Natsuki Takaha*, Yoshihiro Sowa, Ichiro Takeuchi, Takashi Ueda, Saya Ito-Ueda, Yasunori Kimura, Tsuyoshi Iwata, Terukazu Nakamura, Fumiya Hongo, Kazumi Kamoi, Koji Okihara, Akihiro Kawauchi, Tsuneharu Miki, Kyoto, Japan INTRODUCTION AND OBJECTIVES: Prostate cancer (PCa) develops resistance to androgen deprivation therapy and thereafter resistance to docetaxel during progression. We have reported that the level of HMGA1 is low in androgen-dependent PCa cell line (LNCaP) but is high in androgen-independent PCa cell lines (DU145, PC-3), as well as is correlated with the extent of chromosomal aberrations (Can Res, 2002). We also have reported that transfection of HMGA1 into PCa cell lines induces unbalanced chromosomal rearrangement and expression of matrix metalloproteinase 2 (Can Res, 2002; Prostate, 2004). HMGA1 has been reported to be associated with chemotherapyresistance and progression in other types of cancer. These findings have prompted us to examine the effect of HMGA1 on androgen independence and docetaxel-resistance, which are associated with the progression of PCa. METHODS: The following cell lines were examined: LNCaP, LN95 (androgen-independent subline of LNCaP), LNCaP transfected with control vector (LN-EV), LNCaP transfected with HMGA1 (LN-H1), DU145 and PC-3. Expression of HMGA1 and P-glycoprotein (ABCB1) in the PCa cell lines was examined by immunoblot and RT-PCR. The effect of various concentrations of androgen and docetaxel on cell proliferation was determined by WST-8 assay. Apoptosis was evaluated by cell cycle analysis using flow cytometry. RESULTS: The androgen-dependent LNCaP cell line was induced to an androgen-independent subline (LN95) by being maintained for long term in the absence of androgen. The absence of androgen induced a 2.5-fold increase in the level of HMGA1 in the LN95 cells. Androgen deprivation in vitro for 4 days as well as that for 8 days in vivo induced significant increase in the level of HMGA1 in parental LNCaP. We transfected HMGA1 into LNCaP to examine the effect of HMGA1 on androgen and docetaxel sensitivity. The cell proliferation rate of LN-H1 grown in low concentration (0-0.01nM) of DHT was 2-fold higher than that of LN-EV, while both cell lines grew equally well in high concentration (0.1-1nM) of DHT. LN-H1 could form colonies under androgen deprivation, while LN-EV could not. Suppression of HMGA1 in DU145 and PC-3 by siRNA decreased cell proliferation and colony formation by 40% and 10-fold, respectively, and also induced significant apoptosis. LN-H1 was more resistant to docetaxel associated with 17-fold increase of ABCB1 expression compared to LN-EV. CONCLUSIONS: These findings suggest that HMGA1 might play a role during progression of PCa by inducing androgen-independence and docetaxel-resistance. Source of Funding: None

THE JOURNAL OF UROLOGY姞

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207 POLYMORPHISMS IN CYP17A1, CYP3A4 AND CYP3A43 GENES INVOLVED ANDROGEN PATHWAYS AS RISK FACTORS FOR PROSTATE CANCER IN KOREAN POPULATION Jun Hyun Han*, Hwaseong-si, Korea, Republic of; Yong Seong Lee, Soon Chul Myung, Seoul, Korea, Republic of; Seung Wook Lee, Guri, Korea, Republic of; Seung Ok Yang, Seoul, Korea, Republic of INTRODUCTION AND OBJECTIVES: We evaluated genetic variants in the androgen metabolism genes CYP17A1, CYP3A4 and CYP3A43 to determine whether they play a role in the development of prostate cancer in Korean men. METHODS: The study population included 240 pathologically diagnosed cases of prostate cancer and 223 age-matched controls. The Gleason score was classified as low (Gleason sum, 2-6), intermediate (3⫹4, 4⫹3), or high (8-10) grade. The clinical or pathological stages were categorized into localized (T1 or T2N0M0), locally advanced (T3 or T4N0M0), and metastatic (Tx, N⫹ or M⫹) based on the pathological or radiological reports. Among 789 dbSNPs detected, 129 were reported in 2 Asian groups (Han Chinese and Japanese) in the HapMap database (release #27). Only 21 polymorphisms of CYP17A1, CYP3A4 and CYP3A43 were selected based on LDs in Asian (only one SNP if there were absolute LDs (r2⫽1)), locations (SNPs in exons were preferred) and amino acid changes (non-synonymous SNPs were preferred). SNPs were genotyped using TaqMan姞 assay. RESULTS: Average prostate volume were 36.4 ⫾ 15.2 cm3 in the prostate cancer group and 49.0 ⫾ 27.0 cm3 the control group (P ⬍ 0.01). There was no significant difference in mean age between the two groups. Average PSA level of the prostate cancer group was 25.2 ⫾ 87.2 ng/ml and that of the control group was 6.1 ⫾ 6.7 ng/ml (P ⬍ 0.01). 12 sequence variants and 5 major haplotypes were examined in the CYP17A1 gene. 5 sequence variants and 2 major haplotypes were identified in the CYP3A4 gene. 4 sequence variants and 4 major haplotypes were investigated in the CYP3A43 gene. In the logistic regression analysis, haplotype 2 of CYP17A1 (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.04-2.18) was significantly associated with prostate cancer susceptibility in a dominant model. Haplotype 2 of CYP3A4 (OR 1.87, 95% CI 1.02-3.43) was significantly associated with the metastatic potential of prostate cancer related to tumor stage in a co-dominant model. Rs17115149 (OR 1.96, 95% CI 1.04-3.68) and hyplotype 4 (OR 2.01, 95%CI 1.07-4.11) of CYP17A1 showed significant association with the histologic aggressiveness associated with Gleason score in a dominant model. CONCLUSIONS: Genetic variants of CYP17A1 and CYP3A4 may play a role in the development of prostate cancer in Korean men. But understanding the importance of polymorphisms in the androgen pathway genes in Korean men still requires more study. Source of Funding: None

208 Y-BOX BINDING PROTEIN-1 PROMOTES CASTRATION-RESISTANT PROSTATE CANCER GROWTH VIA ANDROGEN RECEPTOR EXPRESSION Masaki Shiota*, Ario Takeuchi, YooHyun Song, Akira Yokomizo, Eiji Kashiwagi, Takeshi Uchiumi, Kentaro Kuroiwa, Katsunori Tatsugami, Fukuoka, Japan; Naohiro Fujimoto, Kitakyushu, Japan; Yoshinao Oda, Seiji Naito, Fukuoka, Japan INTRODUCTION AND OBJECTIVES: Androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer. In several studies, AR was overexpressed in castration-resistant prostate cancer (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. YB-1 is pleiotropic transcription factor which is upregulated in CPRC. We aimed to elucidate the role of YB-1in gain of castration resistance and investigate the possibility of therapeutics targeting YB-1. METHODS: YB-1 and AR expressions in prostate cancer tissues were investigated by immunohistochemistry. YB-1 and AR ex-