Activation of β-catenin cooperates with loss of Pten to drive AR-independent castration-resistant prostate cancer.

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to beta-catenin activation, are refractory to AR-targeted therapies. Here, using clinically relevant murine prostate cancer models, we investigated the significance of beta-catenin activation in prostate cancer progression and treatment resistance. beta-Catenin activation, independent of the cell of origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumors with beta-catenin activation relied on the noncanonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of b-catenin activation, by mediating nuclear localization of NFkBp65 and b-catenin. Overall, WNT/beta-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/beta-catenin signaling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes. Significance: Targeting of both AR and WNT/beta-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.