Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
04
09
2020
accepted:
04
03
2021
revised:
03
03
2021
pubmed:
1
4
2021
medline:
22
3
2022
entrez:
31
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33785871
doi: 10.1038/s41418-021-00773-4
pii: 10.1038/s41418-021-00773-4
pmc: PMC8408186
doi:
Substances chimiques
Myeloid Cell Leukemia Sequence 1 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2589-2600Subventions
Organisme : Wellcome Trust
ID : 204820/Z/16/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Chief Scientist Office [UK]
ID : 2015NOVSPR589
Informations de copyright
© 2021. The Author(s).
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