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Analysis of Wnt Gene Expression in Prostate Cancer

Mutual Inhibition by WNT11 and the Androgen Receptor

¹ Prostate Cancer Research Group, Department of Cancer Cell Biology, Division of Medicine, Imperial College London; ² Department of Histopathology, Division of Investigative Science, Imperial College London; and ³ School of Surgical and Reproductive Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom

The Wnt signaling pathway is aberrantly activated in many tumor types, including those of the prostate, in which ß-catenin accumulates in cell nuclei and acts as a transcriptional coregulator for the androgen receptor. Because activating mutations in the ß-catenin gene are rare in prostate cancer, we have looked for altered expression of other components of the Wnt signaling pathway in prostate cancer cells. Here we determined the expression levels of Wnt family genes in cultured human prostate cells and prostate cancer cell lines. We found that WNT11 expression is elevated in hormone-independent prostate cancer cell lines. Additional analysis indicated that WNT11 expression is also elevated in high-grade prostatic tumors and in hormone-independent xenografts. Growth of hormone-dependent LNCaP cells in hormone-depleted media led to increased WNT11 expression, which was repressed by the synthetic androgen R1881. This repression was inhibited by the antiandrogen bicalutamide, suggesting that androgens negatively regulate WNT11 expression through the androgen receptor. Expression of WNT11 inhibited androgen receptor transcriptional activity and cell growth in androgen-dependent cells but not in androgen-independent cells. WNT11 inhibited activation of the canonical Wnt pathway by WNT3A in HEK 293 cells and inhibited basal ß-catenin/Tcf transcriptional activity in LNCaP cells. However, expression of stabilized ß-catenin did not prevent the inhibition of androgen receptor transcriptional activity by WNT11. Our observations are consistent with a model in which androgen depletion activates WNT11-dependent signals that inhibit androgen-dependent but not androgen-independent cell growth.

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