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CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer
The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121313/ https://www.ncbi.nlm.nih.gov/pubmed/33945523 http://dx.doi.org/10.1371/journal.pgen.1009553 |
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author | Malik, Navdeep Yan, Hualong Yang, Howard H. Ayaz, Gamze DuBois, Wendy Tseng, Yu-Chou Kim, Young-Im Jiang, Shunlin Liu, Chengyu Lee, Maxwell Huang, Jing |
author_facet | Malik, Navdeep Yan, Hualong Yang, Howard H. Ayaz, Gamze DuBois, Wendy Tseng, Yu-Chou Kim, Young-Im Jiang, Shunlin Liu, Chengyu Lee, Maxwell Huang, Jing |
author_sort | Malik, Navdeep |
collection | PubMed |
description | The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53. |
format | Online Article Text |
id | pubmed-8121313 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-81213132021-05-24 CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer Malik, Navdeep Yan, Hualong Yang, Howard H. Ayaz, Gamze DuBois, Wendy Tseng, Yu-Chou Kim, Young-Im Jiang, Shunlin Liu, Chengyu Lee, Maxwell Huang, Jing PLoS Genet Research Article The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53. Public Library of Science 2021-05-04 /pmc/articles/PMC8121313/ /pubmed/33945523 http://dx.doi.org/10.1371/journal.pgen.1009553 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Malik, Navdeep Yan, Hualong Yang, Howard H. Ayaz, Gamze DuBois, Wendy Tseng, Yu-Chou Kim, Young-Im Jiang, Shunlin Liu, Chengyu Lee, Maxwell Huang, Jing CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title | CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title_full | CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title_fullStr | CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title_full_unstemmed | CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title_short | CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer |
title_sort | cbfb cooperates with p53 to maintain tap73 expression and suppress breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121313/ https://www.ncbi.nlm.nih.gov/pubmed/33945523 http://dx.doi.org/10.1371/journal.pgen.1009553 |
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