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

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 i...

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Autores principales: Campbell, Kirsteen J., Mason, Susan M., Winder, Matthew L., Willemsen, Rosalie B. E., Cloix, Catherine, Lawson, Hannah, Rooney, Nicholas, Dhayade, Sandeep, Sims, Andrew H., Blyth, Karen, Tait, Stephen W. G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408186/
https://www.ncbi.nlm.nih.gov/pubmed/33785871
http://dx.doi.org/10.1038/s41418-021-00773-4
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author Campbell, Kirsteen J.
Mason, Susan M.
Winder, Matthew L.
Willemsen, Rosalie B. E.
Cloix, Catherine
Lawson, Hannah
Rooney, Nicholas
Dhayade, Sandeep
Sims, Andrew H.
Blyth, Karen
Tait, Stephen W. G.
author_facet Campbell, Kirsteen J.
Mason, Susan M.
Winder, Matthew L.
Willemsen, Rosalie B. E.
Cloix, Catherine
Lawson, Hannah
Rooney, Nicholas
Dhayade, Sandeep
Sims, Andrew H.
Blyth, Karen
Tait, Stephen W. G.
author_sort Campbell, Kirsteen J.
collection PubMed
description 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.
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spelling pubmed-84081862021-09-16 Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function Campbell, Kirsteen J. Mason, Susan M. Winder, Matthew L. Willemsen, Rosalie B. E. Cloix, Catherine Lawson, Hannah Rooney, Nicholas Dhayade, Sandeep Sims, Andrew H. Blyth, Karen Tait, Stephen W. G. Cell Death Differ Article 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. Nature Publishing Group UK 2021-03-31 2021-09 /pmc/articles/PMC8408186/ /pubmed/33785871 http://dx.doi.org/10.1038/s41418-021-00773-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Campbell, Kirsteen J.
Mason, Susan M.
Winder, Matthew L.
Willemsen, Rosalie B. E.
Cloix, Catherine
Lawson, Hannah
Rooney, Nicholas
Dhayade, Sandeep
Sims, Andrew H.
Blyth, Karen
Tait, Stephen W. G.
Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title_full Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title_fullStr Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title_full_unstemmed Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title_short Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
title_sort breast cancer dependence on mcl-1 is due to its canonical anti-apoptotic function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408186/
https://www.ncbi.nlm.nih.gov/pubmed/33785871
http://dx.doi.org/10.1038/s41418-021-00773-4
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