Frequent down-regulation of ABC transporter genes in prostate cancer

Abstract

Background: ATP-binding cassette (ABC) transporters are transmembrane proteins responsible for the efflux of a wide variety of substrates, including steroid metabolites, through the cellular membranes. For better characterization of the role of ABC transporters in prostate cancer (PCa) development, the profile of ABC transporter gene expression was analyzed in PCa and noncancerous prostate tissues (NPT).

Methods: TaqMan Low Density Array (TLDA) human ABC transporter plates were used for the gene expression profiling in 10 PCa and 6 NPT specimens. ABCB1 transcript level was evaluated in a larger set of PCa cases (N = 78) and NPT (N = 15) by real-time PCR, the same PCa cases were assessed for the gene promoter hypermethylation by methylation-specific PCR.

Results: Expression of eight ABC transporter genes (ABCA8, ABCB1, ABCC6, ABCC9, ABCC10, ABCD2, ABCG2, and ABCG4) was significantly down-regulated in PCa as compared to NPT, and only two genes (ABCC4 and ABCG1) were up-regulated. Down-regulation of ABC transporter genes was prevalent in the TMPRSS2-ERG-negative cases. A detailed analysis of ABCB1 expression confirmed TLDA results: a reduced level of the transcript was identified in PCa in comparison to NPT (p = 0.048). Moreover, the TMPRSS2-ERG-negative PCa cases showed significantly lower expression of ABCB1 in comparison to NPT (p = 0.003) or the fusion-positive tumors (p = 0.002). Promoter methylation of ABCB1 predominantly occurred in PCa and was rarely detected in NPT (p < 0.001).

Conclusions: The study suggests frequent down-regulation of the ABC transporter genes in PCa, especially in the TMPRSS2-ERG-negative tumors.

Fig. 1

Profile of ABC transporter gene expression in prostate cancer (PCa) and noncancerous prostate tissue (NPT). Heat maps represent expression profile of all analyzed (a) and significantly (p < 0.05) deregulated (b) ABC genes. Box plots (c) show expression levels of significantly deregulated ABC genes. The box extends from the 25^th to 75^th percentiles. The line in the middle of the box is plotted at the median. The whiskers indicate the smallest and largest values

Fig. 2

Significant changes (p < 0.05) of ABC transporter gene expression in PCa according to selected variables. F^+/− − TMPRRS2-ERG fusion status; BCR – biochemical recurrence; G7/6 – Gleason score 7/6; pT3/2 – pathological tumor stage 3/2. The box extends from the 25^th to the 75^th percentiles. The line in the middle of the box is plotted at the median. The whiskers indicate the smallest and largest values

Fig. 3

Expression levels (a) and methylation frequency (b) of ABCB1 in prostate tissues. PCa – prostate cancer; NPT – noncancerous prostate tissue; BCR – biochemical recurrence; F^+/− – TMPRRS2-ERG fusion status. The box of figure A extends from the 25^th to the 75^th percentiles. The line in the middle of the box is plotted at the median. The whiskers indicate the smallest and largest values