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.

Figure 1

Influence of SLCO1B3 polymorphism on testosterone transport by Cos-7 transfected with vectors containing SLCO1B3 WT and single/double mutants. Error bars represent the SEM. **, p<0.01 (vector control vs WT, 334G or 699A) and *, p<0.05 (334G/699A vs WT); differences were analyzed by the Tukey's multiple comparison test.

Figure 2

Immunofluorescent localization of OATP1B3. Absent to very faint immunoreactivity was observed in normal tissue and benign prostatic hyperplasia (BPH), while in prostatic cancer the immunoreactivity was strongly increased. (Original magnification × 200)

Figure 3

Kaplan-Meier survival curves in Caucasian prostatic cancer patients grouped by SLCO1B3 haplotypes (variant GG/AA vs. WT TT/GG and heterozygous TG/GA).