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., Mannion, A., Brittain, N., Theodosi, A., Beeby, E., Leszczynska, K. B., …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.