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BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis
Breast cancer patients are commonly treated with taxane (e.g. docetaxel) chemotherapy, despite poor outcomes and eventual disease relapse. We previously identified the Bcl-2-associated death promoter (BAD) as a prognostic indicator of good outcome in taxane-treated breast cancer patients. We also de...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962214/ https://www.ncbi.nlm.nih.gov/pubmed/31942016 http://dx.doi.org/10.1038/s41598-019-57282-1 |
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author | Mann, Jasdeep Yang, Ning Montpetit, Rachel Kirschenman, Raven Lemieux, Hélène Goping, Ing Swie |
author_facet | Mann, Jasdeep Yang, Ning Montpetit, Rachel Kirschenman, Raven Lemieux, Hélène Goping, Ing Swie |
author_sort | Mann, Jasdeep |
collection | PubMed |
description | Breast cancer patients are commonly treated with taxane (e.g. docetaxel) chemotherapy, despite poor outcomes and eventual disease relapse. We previously identified the Bcl-2-associated death promoter (BAD) as a prognostic indicator of good outcome in taxane-treated breast cancer patients. We also demonstrated that BAD expression in human breast carcinoma cells generated larger tumors in mouse xenograft models. These paradoxical results suggest that BAD-expressing tumors are differentially sensitive to taxane treatment. We validated this here and show that docetaxel therapy preferentially reduced growth of BAD-expressing xenograft tumors. We next explored the cellular mechanism whereby BAD sensitizes cells to docetaxel. Taxanes are microtubule inhibiting agents that cause cell cycle arrest in mitosis whereupon the cells either die in mitosis or aberrantly exit (mitotic slippage) and survive as polyploid cells. In response to docetaxel, BAD-expressing cells had lengthened mitotic arrest with a higher proportion of cells undergoing death in mitosis with decreased mitotic slippage. Death in mitosis was non-apoptotic and not dependent on Bcl-XL interaction or caspase activation. Instead, cell death was necroptotic, and dependent on ROS. These results suggest that BAD is prognostic for favourable outcome in response to taxane chemotherapy by enhancing necroptotic cell death and inhibiting the production of potentially chemoresistant polyploid cells. |
format | Online Article Text |
id | pubmed-6962214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69622142020-01-23 BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis Mann, Jasdeep Yang, Ning Montpetit, Rachel Kirschenman, Raven Lemieux, Hélène Goping, Ing Swie Sci Rep Article Breast cancer patients are commonly treated with taxane (e.g. docetaxel) chemotherapy, despite poor outcomes and eventual disease relapse. We previously identified the Bcl-2-associated death promoter (BAD) as a prognostic indicator of good outcome in taxane-treated breast cancer patients. We also demonstrated that BAD expression in human breast carcinoma cells generated larger tumors in mouse xenograft models. These paradoxical results suggest that BAD-expressing tumors are differentially sensitive to taxane treatment. We validated this here and show that docetaxel therapy preferentially reduced growth of BAD-expressing xenograft tumors. We next explored the cellular mechanism whereby BAD sensitizes cells to docetaxel. Taxanes are microtubule inhibiting agents that cause cell cycle arrest in mitosis whereupon the cells either die in mitosis or aberrantly exit (mitotic slippage) and survive as polyploid cells. In response to docetaxel, BAD-expressing cells had lengthened mitotic arrest with a higher proportion of cells undergoing death in mitosis with decreased mitotic slippage. Death in mitosis was non-apoptotic and not dependent on Bcl-XL interaction or caspase activation. Instead, cell death was necroptotic, and dependent on ROS. These results suggest that BAD is prognostic for favourable outcome in response to taxane chemotherapy by enhancing necroptotic cell death and inhibiting the production of potentially chemoresistant polyploid cells. Nature Publishing Group UK 2020-01-15 /pmc/articles/PMC6962214/ /pubmed/31942016 http://dx.doi.org/10.1038/s41598-019-57282-1 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Mann, Jasdeep Yang, Ning Montpetit, Rachel Kirschenman, Raven Lemieux, Hélène Goping, Ing Swie BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title | BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title_full | BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title_fullStr | BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title_full_unstemmed | BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title_short | BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
title_sort | bad sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962214/ https://www.ncbi.nlm.nih.gov/pubmed/31942016 http://dx.doi.org/10.1038/s41598-019-57282-1 |
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