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

Patel, R. et al. (2020) Activation of β-catenin cooperates with loss of Pten to drive AR-independent castration-resistant prostate cancer. Cancer Research, 80(3), pp. 576-590. (doi: 10.1158/0008-5472.CAN-19-1684) (PMID:31719098)

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. 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.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK (A15151, A10419, and A17196), Prostate Cancer UK (PG10-10), and Prostate Cancer Foundation Award.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmad, Professor Imran and Tan, Dr Ee and Tardito, Dr Saverio and Harle, Dr Victoria and Leung, Professor Hing and Repiscak, Dr Peter and Mackay, Dr Gillian and Patel, Dr Rachana and Mrowinska, Ms Agata and Nixon, Mr Colin and Gao, Miss Meiling and Loveridge, Dr Carolyn and Rushworth, Dr Linda and Mui, Mr Ernest and Edwards, Professor Joanne and Ntala, Dr Chara and Malviya, Dr Gaurav and Sansom, Professor Owen
• Authors: Patel, R., Brzezinska, E. A., Repiscak, P., Ahmad, I., Mui, E., Gao, M., Blomme, A., Harle, V., Tan, E. H., Malviya, G., Mrowinska, A., Loveridge, C. J., Rushworth, L. K., Edwards, J., Ntala, C., Nixon, C., Hedley, A., Mackay, G., Tardito, S., Sansom, O. J., and Leung, H. Y.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445
• Published Online: 12 November 2019
• Data DOI: 10.1158/0008-5472.c.6511860.v1

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
165323		Synergistic interaction between Sprouty2 loss and PI3K/AKT activation in prostate carcinogenesis	Hing Leung	Prostate Cancer UK (PROSCANU)	PG10-10	CS - Clinical Research Garscube