SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer

Abstract

Purpose: Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT.

Patients and methods: A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays.

Results: Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P(interaction) = .041).

Conclusion: Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.

Fig 1.

Kaplan-Meier curves of time to progression during androgen deprivation therapy, stratified by (A) genotypes at rs12422149, (B) genotypes at rs1789693, (C) genotypes at rs1077858, and (D) ≤ 1, 2, or 3 unfavorable genotypes of the three SLCO2B1 single nucleotide polymorphisms.

Fig 2.

Sulfated dehydroepiandrosterone (DHEAS) uptake by SLCO2B1 variants. (A) SLCO2B1 mRNA levels in mock transfected LNCaP cells and LNCaP cells transfected with different SLCO2B1 variants. All mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction and normalized by the expression level of glyceraldehyde 3-phosphate dehydrogenase. Values represent the fold differences relative to those in mock transfected cells, which were set as 1.0. (B) Time course of DHEAS uptake. (C) Kinetics of DHEAS uptake (significant differences were observed among three groups, P < .05). Mock, LNCaP transfected with pCMV6-XL4 vector; SLCO2B1-Gln, LNCaP transiently transfected with pCMV-SLCO-312Gln; SLCO2B1-Arg, LNCaP transiently transfected with pCMV-SLCO-312Arg. All experiments were repeated in triplex.

Fig 3.

The impact of SLCO2B1 variants on androgen receptor (AR) –mediated expression and cell growth. (A-D) Quantitative reverse transcriptase polymerase chain reaction analysis of expression levels of prostate-specific antigen (PSA) and AR in various LNCaP and LAPC-4 cell lines with or without sulfated dehydroepiandrosterone (DHEAS). In all experiments, the relative expression levels of PSA and AR in each sample were normalized by the expression level of glyceraldehyde 3-phosphate dehydrogenase. Values represent the fold differences relative to those in mock transfected cells without any drug treatment, which were set as 1.0. (E,F) Cell growth. WST-1 assay was used to determine cell growth. Solid lines and broken lines represent cell cultured in the presence or absence, respectively, of DHEAS. Triplicate experiments were performed for each set. Points, mean (n = 3); bars, standard deviation. Mock, cells transfected with pCMV6-XL4 vector; OD, optical density; SLCO2B1-Gln, cells transfected with the pCMV-SLCO-312Gln; SLCO2B1-Arg, cells transfected with the pCMV-SLCO-312Arg plasmid.

Fig 4.

Kaplan-Meier curves of time to progression during androgen deprivation therapy, stratified by (A,B) genotypes at rs12422149 (SLCO2B1) and rs4149117 (SLCO1B3); (C,D) genotypes at rs1789693 (SLCO2B1) and rs4149117 (SLCO1B3); (E,F) genotypes at rs1077858 (SLCO2B1) and rs4149117 (SLCO1B3); and (G,H) ≤ 1, 2, or 3 unfavorable genotypes of the three SLCO2B1 SNPs and rs4149117 (SLCO1B3).