Repression of the Androgen Receptor by WT1, a Tumor Suppressor Gene
Final rept. 15 Aug 1998-14 Aug 2001
M D ANDERSON CANCER CENTER HOUSTON TX
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The androgen pathway is central to prostate tumorigenesis. An increased risk of higher stage, more aggressive prostate cancer is associated with a more active androgen receptor AR. We are investigating an innovative transcription based mechanism that represses AR activity in vitro. Our hypothesis is that the tumor suppressor gene, WT1, may play a role in prostate tumorigenesis mediated by repression of AR gene expression. To validate our AR promoter data we demonstrated that AR target gene downregulation by WT1 is dependent on an intact DNA binding domain, is mediated by AR and is hormone dependent. Additionally we confirmed our RNA studies showing that WT1 protein expression patterns are inversely related to AR expression. Androgen responsive cell lines express AR but fail to express WT1, while androgen independent lines express WT1 and lack AR, suggesting a correlation with late-stage androgen independence. We have established stably transfected tumor cell lines and have tested the tumorigenicity of these lines with the intent of using them to establish a mouse model of prostate cancer progression. With the correlation of WT1 expression with higher grade disease and the potential to demonstrate WT1 repression of AR expression in mice, we will establish the role of WT1 in the development of androgen independence.
- Anatomy and Physiology
- Medicine and Medical Research