Campbell, K. J. et al. (2021) Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Cell Death and Differentiation, 28(9), pp. 2589-2600. (doi: 10.1038/s41418-021-00773-4) (PMID:33785871) (PMCID:PMC8408186)
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Abstract
High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1’s function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find that MCL-1 is also critical for stem cell activity in human breast cancer cells and high MCL1 expression correlates with stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Blyth, Professor Karen and Cloix, Dr Catherine and Campbell, Dr Kirsteen and Tait, Professor Stephen and Mason, Miss Susan |
| Creator Roles: | Campbell, K. J.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing Tait, S. W.G.Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review and editing Blyth, K.Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review and editing Mason, S. M.Investigation, Methodology Cloix, C.Investigation |
| Authors: | Campbell, K. J., Mason, S. M., Winder, M. L., Willemsen, R. B.E., Cloix, C., Lawson, H., Rooney, N., Dhayade, S., Sims, A. H., Blyth, K., and Tait, S. W.G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Cell Death and Differentiation |
| Publisher: | Nature Research |
| ISSN: | 1350-9047 |
| ISSN (Online): | 1476-5403 |
| Published Online: | 31 March 2021 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Cell Death and Differentiation 28(9): 2589-2600 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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