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BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer

Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of “failed apoptosis” where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed a...

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Autores principales: Pandya, Vrajesh, Githaka, John Maringa, Patel, Namrata, Veldhoen, Richard, Hugh, Judith, Damaraju, Sambasivarao, McMullen, Todd, Mackey, John, Goping, Ing Swie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289861/
https://www.ncbi.nlm.nih.gov/pubmed/32528057
http://dx.doi.org/10.1038/s41419-020-2654-2
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author Pandya, Vrajesh
Githaka, John Maringa
Patel, Namrata
Veldhoen, Richard
Hugh, Judith
Damaraju, Sambasivarao
McMullen, Todd
Mackey, John
Goping, Ing Swie
author_facet Pandya, Vrajesh
Githaka, John Maringa
Patel, Namrata
Veldhoen, Richard
Hugh, Judith
Damaraju, Sambasivarao
McMullen, Todd
Mackey, John
Goping, Ing Swie
author_sort Pandya, Vrajesh
collection PubMed
description Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of “failed apoptosis” where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed apoptosis induces DNA double-strand breaks generating mutations that facilitate tumorigenesis. Whether failed apoptosis is relevant to clinical disease is unknown. BCL-2 interacting killer (BIK) is a stress-induced BH3-only protein that stimulates apoptosis in response to hormone and growth factor deprivation, hypoxia, and genomic stress. It was unclear whether BIK promotes or suppresses tumor survival within the context of breast cancer. We investigated this and show that BIK induces failed apoptosis with limited caspase activation and genomic damage in the absence of extensive cell death. Surviving cells acquire aggressive phenotypes characterized by enrichment of cancer stem-like cells, increased motility and increased clonogenic survival. Furthermore, by examining six independent cohorts of patients (total n = 969), we discovered that high BIK mRNA and protein levels predicted clinical relapse of Estrogen receptor (ER)-positive cancers, which account for almost 70% of all breast cancers diagnosed but had no predictive value for hormone receptor-negative (triple-negative) patients. Thus, this study identifies BIK as a biomarker for tumor recurrence of ER-positive patients and provides a potential mechanism whereby failed apoptosis contributes to cancer aggression.
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spelling pubmed-72898612020-06-15 BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer Pandya, Vrajesh Githaka, John Maringa Patel, Namrata Veldhoen, Richard Hugh, Judith Damaraju, Sambasivarao McMullen, Todd Mackey, John Goping, Ing Swie Cell Death Dis Article Apoptosis is fundamental to normal animal development and is the target for many anticancer therapies. Recent studies have explored the consequences of “failed apoptosis” where the apoptotic program is initiated but does not go to completion and does not cause cell death. Nevertheless, this failed apoptosis induces DNA double-strand breaks generating mutations that facilitate tumorigenesis. Whether failed apoptosis is relevant to clinical disease is unknown. BCL-2 interacting killer (BIK) is a stress-induced BH3-only protein that stimulates apoptosis in response to hormone and growth factor deprivation, hypoxia, and genomic stress. It was unclear whether BIK promotes or suppresses tumor survival within the context of breast cancer. We investigated this and show that BIK induces failed apoptosis with limited caspase activation and genomic damage in the absence of extensive cell death. Surviving cells acquire aggressive phenotypes characterized by enrichment of cancer stem-like cells, increased motility and increased clonogenic survival. Furthermore, by examining six independent cohorts of patients (total n = 969), we discovered that high BIK mRNA and protein levels predicted clinical relapse of Estrogen receptor (ER)-positive cancers, which account for almost 70% of all breast cancers diagnosed but had no predictive value for hormone receptor-negative (triple-negative) patients. Thus, this study identifies BIK as a biomarker for tumor recurrence of ER-positive patients and provides a potential mechanism whereby failed apoptosis contributes to cancer aggression. Nature Publishing Group UK 2020-06-11 /pmc/articles/PMC7289861/ /pubmed/32528057 http://dx.doi.org/10.1038/s41419-020-2654-2 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
Pandya, Vrajesh
Githaka, John Maringa
Patel, Namrata
Veldhoen, Richard
Hugh, Judith
Damaraju, Sambasivarao
McMullen, Todd
Mackey, John
Goping, Ing Swie
BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title_full BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title_fullStr BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title_full_unstemmed BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title_short BIK drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of ER-positive breast cancer
title_sort bik drives an aggressive breast cancer phenotype through sublethal apoptosis and predicts poor prognosis of er-positive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289861/
https://www.ncbi.nlm.nih.gov/pubmed/32528057
http://dx.doi.org/10.1038/s41419-020-2654-2
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