Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function

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 > Institute 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172494Targeting MCL-1 in breast cancerStephen TaitBreast Cancer Now (BRCANNOW)2015NovSPR589Institute of Cancer Sciences
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences
172007Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145Institute of Cancer Sciences