Renal cell carcinoma is the sixth-leading cause of cancer death. Resistance to radiation and classical chemotherapy is often observed in metastatic RCC, a problem that is directly related to the fact that the molecular events leading to disease onset and progression are not well understood. Metastatic RCC typically results in death in less than a year. It is our long term goal to identify and characterize the molecular pathways leading to conventional RCC to enable the design of more effective, targeted therapies. One candidate is the Wnt/β-catenin pathway. While activation of the β-catenin pathway in cRCC has remained controversial, our data indicate that β-catenin transcriptional targets are up-regulated in both cRCC tissue and cell lines. We have also observed nuclear localization of β-catenin in patient samples, a hallmark of β-catenin pathway activation. Furthermore, our clinical data indicate that loss of a negative regulatory protein, secreted frizzled-related protein 1 (sFRP1), may be responsible for activation of Wnt/β-catenin activity. Indeed, loss or repression of sFRP1 expression was observed in 100% of 53 patients tested. This is the first report of loss of sFRP1 expression in patients diagnosed with cRCC; this occurs in early stage cRCC, suggesting that it may be an important event in renal carcinogenesis. A human cRCC cell model recapitulated these observations and confirmed activation of the Wnt/β-catenin pathway. Treatment of cRCC cells with 5’aza-deoxycytidine suggested that loss of sFRP1 is due to promoter hypermethylation. Moreover, global demethylation resulted in decreased expression of the β-catenin transcriptional targets VEGF and c-Myc. In order to test the hypothesis that activation of the Wnt/β-catenin pathway in cRCC is due to loss of sFRP1, we are currently stably re-expressing sFRP1 in a cRCC cell line and inhibiting expression of sFRP1 in a normal renal epithelial cell line. The effects of manipulating sFRP1 expression will be measured by evaluating β-catenin transcriptional activity, cell phenotype, and tumor formation in a nude mouse model. These studies will define the role of aberrant sFRP1 and β-catenin signaling in cRCC.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]