WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

Poujade, Flore-Anne; Mannion, Aarren; Brittain, Nicholas; Theodosi, Andrew; Beeby, Ellie; Leszczynska, Katarzyna B.; Hammond, Ester M.; Greenman, John; Cawthorne, Christopher; Pires, Isabel M.

Abstract

© 2018 Cancer Research UK. Background: Metastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread. Methods: In this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo. Results: High WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential. Conclusions: Our data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients.

Citation

Poujade, F.-A., Mannion, A., Brittain, N., Theodosi, A., Beeby, E., Leszczynska, K. B., Hammond, E. M., Greenman, J., Cawthorne, C., & Pires, I. M. (2018). WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer. The British Journal of Cancer, 118(9), 1229-1237. https://doi.org/10.1038/s41416-018-0056-3

• Journal Article Type: Article
• Acceptance Date: Feb 9, 2018
• Online Publication Date: Mar 15, 2018
• Publication Date: 2018-05
• Deposit Date: Aug 8, 2018
• Publicly Available Date: Sep 16, 2018
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 118
• Issue: 9
• Pages: 1229-1237
• DOI: https://doi.org/10.1038/s41416-018-0056-3
• Keywords: Cancer Research; Oncology
• Public URL: https://hull-repository.worktribe.com/output/617535
• Publisher URL: https://www.nature.com/articles/s41416-018-0056-3
• Additional Information: Received: 23 January 2018; Revised: 12 February 2018; Accepted: 21 February 2018; First Online: 15 March 2018; : The authors declare no competing interests.