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Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration
Breast cancer consists of a range of tumor subtypes with different clinical characteristics, disease prognosis, and treatment-response. Luminal breast cancer has the best prognosis while basal-like breast cancer (BLBC) represents the worst subtype. Transforming growth factor-beta (TGFβ) plays a prom...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670207/ https://www.ncbi.nlm.nih.gov/pubmed/29101386 http://dx.doi.org/10.1038/s41598-017-14549-9 |
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author | Hachim, Ibrahim Y. Villatoro, Manuel Canaff, Lucie Hachim, Mahmood Y. Boudreault, Julien Haiub, Halema Ali, Suhad Lebrun, Jean-Jacques |
author_facet | Hachim, Ibrahim Y. Villatoro, Manuel Canaff, Lucie Hachim, Mahmood Y. Boudreault, Julien Haiub, Halema Ali, Suhad Lebrun, Jean-Jacques |
author_sort | Hachim, Ibrahim Y. |
collection | PubMed |
description | Breast cancer consists of a range of tumor subtypes with different clinical characteristics, disease prognosis, and treatment-response. Luminal breast cancer has the best prognosis while basal-like breast cancer (BLBC) represents the worst subtype. Transforming growth factor-beta (TGFβ) plays a prominent role in stimulating the migration and invasion of malignant breast cancer cells contributing to tumor progression. In this study, we identified the Ephrin type-A receptor 4 (EPHA4) as a novel target of TGFβ in breast cancer. Moreover, we show that TGFβ induction of EPHA4 gene expression is specific to basal-like tumors and is required for TGFβ-mediated cell migration. We further addressed the mechanism and found EPHA4 to be required for TGFβ-mediated cell migration in breast cancer through TGFβ-induced short term and long term activation of RhoGTPases. Finally, our data revealed a strong association between high EPHA4 expression and advanced tumor stage, aggressive BLBC molecular subtype and poor prognosis. Importantly, we found significant co-expression of EPHA4 and the TGFβ receptor type-2 (TGFβR2) in breast cancer subtypes associated with increased tumor relapse and drug resistance. Together, this study highlight the important role of the TGFβ/EPHA4 signaling axis in mediating tumor aggressiveness and poor patient survival in human breast cancer. |
format | Online Article Text |
id | pubmed-5670207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56702072017-11-15 Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration Hachim, Ibrahim Y. Villatoro, Manuel Canaff, Lucie Hachim, Mahmood Y. Boudreault, Julien Haiub, Halema Ali, Suhad Lebrun, Jean-Jacques Sci Rep Article Breast cancer consists of a range of tumor subtypes with different clinical characteristics, disease prognosis, and treatment-response. Luminal breast cancer has the best prognosis while basal-like breast cancer (BLBC) represents the worst subtype. Transforming growth factor-beta (TGFβ) plays a prominent role in stimulating the migration and invasion of malignant breast cancer cells contributing to tumor progression. In this study, we identified the Ephrin type-A receptor 4 (EPHA4) as a novel target of TGFβ in breast cancer. Moreover, we show that TGFβ induction of EPHA4 gene expression is specific to basal-like tumors and is required for TGFβ-mediated cell migration. We further addressed the mechanism and found EPHA4 to be required for TGFβ-mediated cell migration in breast cancer through TGFβ-induced short term and long term activation of RhoGTPases. Finally, our data revealed a strong association between high EPHA4 expression and advanced tumor stage, aggressive BLBC molecular subtype and poor prognosis. Importantly, we found significant co-expression of EPHA4 and the TGFβ receptor type-2 (TGFβR2) in breast cancer subtypes associated with increased tumor relapse and drug resistance. Together, this study highlight the important role of the TGFβ/EPHA4 signaling axis in mediating tumor aggressiveness and poor patient survival in human breast cancer. Nature Publishing Group UK 2017-11-03 /pmc/articles/PMC5670207/ /pubmed/29101386 http://dx.doi.org/10.1038/s41598-017-14549-9 Text en © The Author(s) 2017 https://creativecommons.org/licenses/by/4.0/ 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hachim, Ibrahim Y. Villatoro, Manuel Canaff, Lucie Hachim, Mahmood Y. Boudreault, Julien Haiub, Halema Ali, Suhad Lebrun, Jean-Jacques Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title | Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title_full | Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title_fullStr | Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title_full_unstemmed | Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title_short | Transforming Growth Factor-beta Regulation of Ephrin Type-A Receptor 4 Signaling in Breast Cancer Cellular Migration |
title_sort | transforming growth factor-beta regulation of ephrin type-a receptor 4 signaling in breast cancer cellular migration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670207/ https://www.ncbi.nlm.nih.gov/pubmed/29101386 http://dx.doi.org/10.1038/s41598-017-14549-9 |
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