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Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer

Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of...

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Autores principales: Abdeen, Suhaib K., Ben-David, Uri, Shweiki, Aya, Maly, Bella, Aqeilan, Rami I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079009/
https://www.ncbi.nlm.nih.gov/pubmed/30082886
http://dx.doi.org/10.1038/s41419-018-0896-z
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author Abdeen, Suhaib K.
Ben-David, Uri
Shweiki, Aya
Maly, Bella
Aqeilan, Rami I.
author_facet Abdeen, Suhaib K.
Ben-David, Uri
Shweiki, Aya
Maly, Bella
Aqeilan, Rami I.
author_sort Abdeen, Suhaib K.
collection PubMed
description Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of WWOX in driving breast carcinogenesis remains unknown. Here we report that ablation of Wwox in mammary tumor-susceptible mice results in increased tumorigenesis, and that the resultant tumors resemble human BLBC. Interestingly, copy number loss of Trp53 and downregulation of its transcript levels were observed in the Wwox knockout tumors. Moreover, tumors isolated from Wwox and Trp53 mutant mice were indistinguishable histologically and transcriptionally. Finally, we find that deletion of TP53 and WWOX co-occurred and is associated with poor survival of breast cancer patients. Altogether, our data uncover an essential role for WWOX as a bona fide breast cancer tumor suppressor through the maintenance of p53 stability.
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spelling pubmed-60790092018-08-07 Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer Abdeen, Suhaib K. Ben-David, Uri Shweiki, Aya Maly, Bella Aqeilan, Rami I. Cell Death Dis Article Inactivation of WW domain-containing oxidoreductase (WWOX), the gene product of the common fragile site FRA16D, is a common event in breast cancer and is associated with worse prognosis of triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC). Despite recent progress, the role of WWOX in driving breast carcinogenesis remains unknown. Here we report that ablation of Wwox in mammary tumor-susceptible mice results in increased tumorigenesis, and that the resultant tumors resemble human BLBC. Interestingly, copy number loss of Trp53 and downregulation of its transcript levels were observed in the Wwox knockout tumors. Moreover, tumors isolated from Wwox and Trp53 mutant mice were indistinguishable histologically and transcriptionally. Finally, we find that deletion of TP53 and WWOX co-occurred and is associated with poor survival of breast cancer patients. Altogether, our data uncover an essential role for WWOX as a bona fide breast cancer tumor suppressor through the maintenance of p53 stability. Nature Publishing Group UK 2018-08-06 /pmc/articles/PMC6079009/ /pubmed/30082886 http://dx.doi.org/10.1038/s41419-018-0896-z Text en © The Author(s) 2018 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
Abdeen, Suhaib K.
Ben-David, Uri
Shweiki, Aya
Maly, Bella
Aqeilan, Rami I.
Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title_full Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title_fullStr Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title_full_unstemmed Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title_short Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
title_sort somatic loss of wwox is associated with tp53 perturbation in basal-like breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079009/
https://www.ncbi.nlm.nih.gov/pubmed/30082886
http://dx.doi.org/10.1038/s41419-018-0896-z
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