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The overall hypothesis to be tested was that qualitative and/or quantitative differences in the expression of the Wilms Tumor Gene (WTl) would alter the behavior of human prostate cancer cells especially with regard to proliferation. During this study we discovered a novel transcript of WTl (TR-WTI) consisting of portions of intron 5 and exons 6-10. Analysis of prostate cancer cell lines transfected with wild-type WT 1 (+1 7,+KTS) revealed that induction of WT 1 expression could suppress transcription of the insulin-like growth factor receptor (IGFR) promoter, which was linked to decreased IGF responsiveness. In contrast, transfection of the TR-WTl did not affect endogeneous transcription of either IGFR or the epidermal growth factor receptor (EGFR). M2205 cells transfected with TR-WTl (-KTS) doubled significantly faster in vitro and were more tumorigenic in vivo than controls or cells transfected with TR-Wtl (+KTS). Analysis of microdissected human prostate cancers revealed that WT1 or TR-WT1 mRNA was detected in 18/32 malignant glands. Collectively, these results suggest that WTl and/or TR-WT1 products may play an unusual role in prostate cancer behavior.