Abstract C95: Role of 5-alpha reductase inhibitor in regulating ETS transcription factors in prostate cell lines

Abstract

Abstract Androgens play a crucial role in normal and cancerous growth and hence the androgenic pathway has become an important target of therapeutic intervention. We have discovered the gene fusions of the 5′-untranslated region (UTR) of androgen regulated gene TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4 (17q21), in the majority of prostate cancers. This provides a mechanism for over-expression of ETS genes leading to tumor progression. Dutasteride (Avodart®) is a 5-alpha-reductase inhibitor that blocks the synthesis of the intracellular androgen dihydrotestosterone (DHT). Here we tested the effect of dutasteride on TMPRSS2-ERG fusion positive VCaP cells. Our data showed 5-alpha-reductase SRD5A1 and SRD5A3 isoenzymes are highly expressed in metastases as compared to benign and prostate cancer cases. On the contrary, SRD5A2 is highly expressed in benign and prostate cancer cases. We found dutasteride treated VCaP cells at 10 and 50uM concentration showed a significant decrease in cell proliferation along with distinct morphological changes. Cells treated with synthetic androgen R1881, testosterone or DHT showed a drastic increase in invading cells, while dutasteride at 50uM concentration showed a significant decrease in cell invasion alone or in combination with testosterone or DHT. VCaP cells grown under androgen deprivation or treated with 10uM dutasteride showed reduction in ERG and PSA expression. Conversely, cells treated with testosterone or DHT resulted in a marked induction of PSA and ERG as anticipated, while in cells pre-treated with dutasteride, there was a further decrease in the ERG and PSA expression. Addition of testosterone to cells treated with dutasteride slightly increased the ERG expression. Our data clearly suggest that inhibition of 5-alpha reductase by dutasteride significantly reduces the fusion gene expression. We further tested our hypothesis in an in vivo VCaP-luciferase xenograft model. We found bicalutamide alone showed a decrease in tumor volume in VCaP-Luc xenografts, whereas the combination of dutasteride and bicalutamide reduced tumor burden significantly. Our findings provide insights into the function of dutasteride within the tumor microenvironment, potentially allowing for development of therapeutics that can be used in combination with this drug to further enhance its effectiveness in ETS positive prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C95.