Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes.
BACKGROUND
Metastases from men with castration-resistant prostate cancer (CRPC) harbor increased tumoral androgens versus untreated prostate cancers. This may reflect steroid uptake by OATP (organic anion transporting polypeptide)/SLCO transporters. We evaluated SLCO gene expression in CRPC metastases and determined whether prostate cancer outcomes are associated with single nucleotide polymorphisms (SNP) in SLCO2B1 and SLCO1B3, transporters previously shown to mediate androgen uptake.


METHODS
Transcripts encoding eleven SLCO genes were analyzed in untreated prostate cancer and in metastatic CRPC tumors obtained by rapid autopsy. SNPs in SLCO2B1 and SLCO1B3 were genotyped in a population-based cohort of 1,309 Caucasian prostate cancer patients. Median survival follow-up was 7.0 years (0.77-16.4). The risk of prostate cancer recurrence/progression and prostate cancer-specific mortality (PCSM) was estimated with Cox proportional hazards analysis.


RESULTS
Six SLCO genes were highly expressed in CRPC metastases versus untreated prostate cancer, including SLCO1B3 (3.6-fold; P = 0.0517) and SLCO2B1 (5.5-fold; P = 0.0034). Carriers of the variant alleles SLCO2B1 SNP rs12422149 (HR: 1.99; 95% CI: 1.11-3.55) or SLCO1B3 SNP rs4149117 (HR: 1.76; 95% CI: 1.00-3.08) had an increased risk of PCSM.


CONCLUSIONS
CRPC metastases show increased expression of SLCO genes versus primary prostate cancer. Genetic variants of SLCO1B3 and SLCO2B1 are associated with PCSM. Expression and genetic variation of SLCO genes which alter androgen uptake may be important in prostate cancer outcomes.


CONCLUSIONS
OATP/SLCO genes may be potential biomarkers for assessing risk of PCSM. Expression and genetic variation in these genes may allow stratification of patients to more aggressive hormonal therapy or earlier incorporation of nonhormonal-based treatment strategies.
Department of Urology, University of Washington, Seattle, WA, USA.
Jonathan L
JL
Wright
Erika M
EM
Kwon
Elaine A
EA
Ostrander
R Bruce
RB
Montgomery
Daniel W
DW
Lin
Robert
R
Vessella
Janet L
JL
Stanford
Elahe A
EA
Mostaghel
D000328:Adult; D000368:Aged; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009919:Orchiectomy; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D012307:Risk Factors; D018426:SEER Program; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016896:Treatment Outcome
D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
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