SLCO2B3 is involved in the uptake of hormones including testosterone (T) and is expressed in liver and cancer cells. SLCO2B1 and SLCO1B3 are both polymorphic and two single nucleotide polymorphisms (SNPs) in SLCOB3, rs4149117 and rs7311358 are in complete linkage disequilibrium, exhibiting different T transport efficiencies. In the online edition of the Journal of Clinical Oncology, Dr. Ming Yang and colleagues studied the roles of SLCO2B1 and SLCO1B3 in prostate cancer (CaP) progression, specifically related to androgen deprivation therapy (ADT). They hypothesized that genetic variants in SLCO2B1 and SLCO1B3 may influence time to progression (TTP) of ADT and resistance to this form of therapy in CaP.
The study cohort included 538 CaP patients treated with ADT. TTP was assessed using PSA, defined as the time from ADT initiation to the date of PSA progression. Three SNPs in SLCO2B1 were associated with TTP during ADT in univariate analysis. The differences in median TTP during ADT for the genotypes were 10 months for rs12422149, 7 months for rs1789693, and 12 months for rs1077858. All three remained significant in multivariate analysis that included clinical variables. An additive affect across the 3 SNPs was found. For example, a 12-month shorter TTP was observed for those with 2 risk genotypes compared to one or none. They transfected plasmids expressing variants into LNCaP cells and this resulted in increased cellular import of DHEAS. Increasing the DHEAS level
- upregulated the transactivation of PSA,
- increased the expression level of AR, and
- increased cellular growth rate 1.4-fold.
They validated these findings in the LAPC-4 cell line. In patient samples they found a gene-gene interaction between SLCO2B1 and SLCO1B3. The interaction correlated with a greater than 2-year difference in median TTP. This suggests that the SLCO1B3 genotype could significantly modify rates of disease progression for those who harbor the SLCO2B1 risk genotype.
Yang M, Xie W, Mostaghel E, Nakabayashi M, Werner L, Sun T, Pomerantz M, Freedman M, Ross R, Regan M, Sharifi N, Figg WD, Balk S, Brown M, Taplin ME, Oh WK, Lee GS, Kantoff PW
J Clin Oncol. 2011 Jun 20;29(18):2565-73
10.1200/JCO.2010.31.2405
PubMed Abstract
PMID: 21606417
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