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. Prostate cancer patients with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies. Here using clinically relevant murine prostate cancer models, we investigated the significance of β-catenin activation in prostate cancer progression and treatment resistance. β-catenin activation, independent of the cell-of-origin, cooperated with Pten loss to drive AR-independent castration-resistant prostate cancer. Prostate tumours with β-catenin activation relied on the non-canonical WNT ligand WNT5a for sustained growth. WNT5a repressed AR expression and maintained the expression of c-Myc, an oncogenic effector of β-catenin activation, by mediating nuclear localization of NFƙBp65 and β-catenin. Overall, WNT/β-catenin and AR signalling are reciprocally inhibited. Therefore, inhibiting WNT/β-catenin signalling by limiting WNT secretion in concert with AR inhibition may be useful for treating prostate cancers with alterations in WNT pathway genes.