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ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts

The ATR protein kinase is a master regulator of the cellular responses to DNA damage and replication stresses. Despite these crucial physiological roles, the implication of ATR in human carcinogenesis remains elusive. We have shown here that the ATR level is reduced in most cancer-associated fibrobl...

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Autores principales: Al-Ansari, Mysoon M., Aboussekhra, Abdelilah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205174/
https://www.ncbi.nlm.nih.gov/pubmed/30410668
http://dx.doi.org/10.18632/oncotarget.26159
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author Al-Ansari, Mysoon M.
Aboussekhra, Abdelilah
author_facet Al-Ansari, Mysoon M.
Aboussekhra, Abdelilah
author_sort Al-Ansari, Mysoon M.
collection PubMed
description The ATR protein kinase is a master regulator of the cellular responses to DNA damage and replication stresses. Despite these crucial physiological roles, the implication of ATR in human carcinogenesis remains elusive. We have shown here that the ATR level is reduced in most cancer-associated fibroblasts (CAFs) as compared to their adjacent normal counterparts. Importantly, specific ATR knockdown activated breast fibroblasts, and enhanced their paracrine pro-carcinogenic effects via strong increase in the expression/secretion of SDF-1 and IL-6. Furthermore, ATR-deficient fibroblasts enhanced tumor growth and aggressiveness in orthotopic breast tumor xenografts. On the other hand, ectopic expression of ATR suppressed the expression/secretion of several cancer-promoting proteins such as IL-6, TGF-β1 and SDF-1, and inhibited the migration and invasion capacities of breast myofibroblast cells. Furthermore, ATR up-regulation in active breast fibroblasts reduced their paracrine pro-migratory/-invasive effects on breast cancer cells. Interestingly, the cancer promoting effects of ATR-deficient cells were repressed by ectopic expression of the ATR effector p53. These results indicate that ATR is a major target of cancer cells in breast fibroblasts wherein this protein kinase represses both autocrine and paracrine pro-carcinogenic effects. This indicates that the ATR status in these cells could be of great prognostic/diagnostic values.
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spelling pubmed-62051742018-11-08 ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts Al-Ansari, Mysoon M. Aboussekhra, Abdelilah Oncotarget Research Paper The ATR protein kinase is a master regulator of the cellular responses to DNA damage and replication stresses. Despite these crucial physiological roles, the implication of ATR in human carcinogenesis remains elusive. We have shown here that the ATR level is reduced in most cancer-associated fibroblasts (CAFs) as compared to their adjacent normal counterparts. Importantly, specific ATR knockdown activated breast fibroblasts, and enhanced their paracrine pro-carcinogenic effects via strong increase in the expression/secretion of SDF-1 and IL-6. Furthermore, ATR-deficient fibroblasts enhanced tumor growth and aggressiveness in orthotopic breast tumor xenografts. On the other hand, ectopic expression of ATR suppressed the expression/secretion of several cancer-promoting proteins such as IL-6, TGF-β1 and SDF-1, and inhibited the migration and invasion capacities of breast myofibroblast cells. Furthermore, ATR up-regulation in active breast fibroblasts reduced their paracrine pro-migratory/-invasive effects on breast cancer cells. Interestingly, the cancer promoting effects of ATR-deficient cells were repressed by ectopic expression of the ATR effector p53. These results indicate that ATR is a major target of cancer cells in breast fibroblasts wherein this protein kinase represses both autocrine and paracrine pro-carcinogenic effects. This indicates that the ATR status in these cells could be of great prognostic/diagnostic values. Impact Journals LLC 2018-10-05 /pmc/articles/PMC6205174/ /pubmed/30410668 http://dx.doi.org/10.18632/oncotarget.26159 Text en Copyright: © 2018 Al-Ansari and Aboussekhra http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Al-Ansari, Mysoon M.
Aboussekhra, Abdelilah
ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title_full ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title_fullStr ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title_full_unstemmed ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title_short ATR suppresses the pro-tumorigenic functions of breast stromal fibroblasts
title_sort atr suppresses the pro-tumorigenic functions of breast stromal fibroblasts
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205174/
https://www.ncbi.nlm.nih.gov/pubmed/30410668
http://dx.doi.org/10.18632/oncotarget.26159
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