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Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer.

ABSTRACT: PURPOSE:The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of SLCO1B3 haplotype on clinical outcome of Caucasian patients with androgen-independent prostatic cancer. EXPERIMENTAL DESIGN:SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, whereas testosterone transport was analyzed in Cos-7 cells transfected with WT, 334G, and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy, and the relationship between SLCO1B3 haplotypes and survival was examined in patients. RESULTS:Cells transfected with wild-type (334T/699G) SLCO1B3, or with a vector containing either the 334G or 699A variants, actively transported testosterone, whereas its uptake was impaired in cells transfected with a gene carrying both 334G and 699A single nucleotide polymorphisms. Prostatic cancer overexpresses OATP1B3 compared with normal or benign hyperplastic tissue; patients with SLCO1B3 334GG/699AA haplotype showed longer median survival (8.5 versus 6.4 years; P = 0.020) and improved survival probability at 10 years (42% versus 23%; P < 0.023) than patients carrying TT/AA and TG/GA haplotypes. CONCLUSIONS:The common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostatic cancer.

SUBMITTER: Hamada A

PROVIDER: S-EPMC2701141 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer.

Hamada Akinobu A Sissung Tristan T Price Douglas K DK Danesi Romano R Chau Cindy H CH Sharifi Nima N Venzon David D Maeda Kenji K Nagao Keisuke K Sparreboom Alex A Mitsuya Hiroaki H Dahut William L WL Figg William D WD

Clinical cancer research : an official journal of the American Association for Cancer Research 20080601 11

<h4>Purpose</h4>The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of SLCO1 ...[more]

PMID: 18519758

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Project description:What is already known about this subjectSLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel. The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing.What this study addsThe SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n= 50). Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition. This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMS To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n= 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients.MethodsGenomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK.ResultsA strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,∞)): r(2) = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P= 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3'-untranslated region which may influence the transport characteristics of SLCO1B3.ConclusionsThis study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.

Project description:BackgroundBenign prostatic hyperplasia (BPH) is a common urological disorder reported among ageing men.ObjectiveThe study assessed histoprotective effect of lime essential oil (LEO) in a rat model of testosterone-induced benign prostatic hyperplasia (BPH) and evaluated its ability to reverse testosterone-mediated changes in the testis, kidney, and liver.Materials and methodsAdult Sprague Dawley (aged 12 weeks, 240-390 g) male rats were intramuscularly injected with testosterone enanthate (TE) (10 mg/kg) reconstituted in olive oil for ten days to establish benign prostatic hyperplasia (serum PSA level ≥ 1.24 ng/ml) in. After confirmation of BPH (sustained serum PSA level ≥ 1.24 ng/ml), rats in all groups (LEO: 30, 100, and 300 mg/kg, po, n = 6; finasteride: 15 mg/kg, po, n = 6) except model (BPH without treatment) and sham (no BPH and no treatment) groups were treated for 21 days. At the end of treatment, rats were anesthetised and blood was collected via cardiac puncture to determine serum PSA and total antioxidant capacity (TAC) levels. The prostate gland, testis, kidney, and liver were harvested, weighed, histologically processed and stained with H&E.ResultsLEO- and finasteride-treated groups recorded lesser mean prostatic weights relative to their model group. Baseline mean serum PSA level of LEO- and finasteride-treated groups reduced significantly (p < 0.05) relative to model group. Serum TAC levels were also higher in LEO- and finasteride-treated groups relative to model group. LEO-treated groups had less thickened glandular epithelium, smaller acini, fewer prostatic secretions and more fibromuscular stroma relative to model group. LEO and finasteride treatment produced improved histomorphological characteristics of testis, kidney, and liver compared to model group.ConclusionBy the current results, Citrus aurantifolia LEO may possess active agents that can be explored for translational medicine against BPH.

Dataset Information

Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer.

Publications

Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer.

Similar Datasets

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