Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer.

Abstract

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 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 tumors with β-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 β-catenin activation, by mediating nuclear localization of NFκBp65 and β-catenin. Overall, WNT/β-catenin and AR signaling are reciprocally inhibited. Therefore, inhibiting WNT/β-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/β-catenin signaling may be required to treat prostate cancers that exhibit alterations of the WNT pathway.

• Authors: Rachana Patel, Elspeth A Brzezinska, Peter Repiscak, Imran Ahmad, Ernest Mui, Meiling Gao, Arnaud Blomme, Victoria Harle, Ee Hong Tan, Gaurav Malviya, Agata Mrowinska, Carolyn J Loveridge, Linda K Rushworth, Joanne Edwards, Chara Ntala, Colin Nixon, Ann Hedley, Gillian Mackay, Saverio Tardito, Owen J Sansom, Hing Y Leung
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 3 Pg. 576-590 (02 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 31719098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• AR protein, human
• Androgen Receptor Antagonists
• Biomarkers, Tumor
• CTNNB1 protein, human
• Receptors, Androgen
• WNT5A protein, human
• Wnt-5a Protein
• beta Catenin
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Androgen Receptor Antagonists (pharmacology)
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• PTEN Phosphohydrolase (deficiency)
• Prognosis
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, metabolism, pathology)
• Receptors, Androgen (genetics, metabolism)
• Survival Rate
• Tumor Cells, Cultured
• Wnt-5a Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)