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Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data
INTRODUCTION: WNT signaling is a complex process comprising multiple pathways: the canonical β-catenin-dependent pathway and several alternative non-canonical pathways that act in a β-catenin-independent manner. Representing these intricate signaling mechanisms through bioinformatic approaches is ch...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669165/ https://www.ncbi.nlm.nih.gov/pubmed/26632845 http://dx.doi.org/10.1371/journal.pone.0144014 |
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author | Bayerlová, Michaela Klemm, Florian Kramer, Frank Pukrop, Tobias Beißbarth, Tim Bleckmann, Annalen |
author_facet | Bayerlová, Michaela Klemm, Florian Kramer, Frank Pukrop, Tobias Beißbarth, Tim Bleckmann, Annalen |
author_sort | Bayerlová, Michaela |
collection | PubMed |
description | INTRODUCTION: WNT signaling is a complex process comprising multiple pathways: the canonical β-catenin-dependent pathway and several alternative non-canonical pathways that act in a β-catenin-independent manner. Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e.g. high-throughput data. RESULTS: In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases. The data were assembled to construct computationally suitable models of different WNT signaling cascades in the form of directed signaling graphs. This resulted in four networks representing canonical WNT signaling, non-canonical WNT signaling, the inhibition of canonical WNT signaling and the regulation of WNT signaling pathways, respectively. Furthermore, these networks were integrated with microarray and RNA sequencing data to gain deeper insight into the underlying biology of gene expression differences between MCF-7 and MDA-MB-231 breast cancer cell lines, representing weakly and highly invasive breast carcinomas, respectively. Differential genes up-regulated in the MDA-MB-231 compared to the MCF-7 cell line were found to display enrichment in the gene set originating from the non-canonical network. Moreover, we identified and validated differentially regulated modules representing canonical and non-canonical WNT pathway components specific for the aggressive basal-like breast cancer subtype. CONCLUSIONS: In conclusion, we demonstrated that these newly constructed WNT networks reliably reflect distinct WNT signaling processes. Using transcriptomic data, we shaped these networks into comprehensive modules of the genes implicated in the aggressive basal-like breast cancer subtype and demonstrated that non-canonical WNT signaling is important in this context. The topology of these networks can be further refined in the future by integration with complementary data such as protein-protein interactions, in order to gain greater insight into signaling processes. |
format | Online Article Text |
id | pubmed-4669165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46691652015-12-10 Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data Bayerlová, Michaela Klemm, Florian Kramer, Frank Pukrop, Tobias Beißbarth, Tim Bleckmann, Annalen PLoS One Research Article INTRODUCTION: WNT signaling is a complex process comprising multiple pathways: the canonical β-catenin-dependent pathway and several alternative non-canonical pathways that act in a β-catenin-independent manner. Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e.g. high-throughput data. RESULTS: In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases. The data were assembled to construct computationally suitable models of different WNT signaling cascades in the form of directed signaling graphs. This resulted in four networks representing canonical WNT signaling, non-canonical WNT signaling, the inhibition of canonical WNT signaling and the regulation of WNT signaling pathways, respectively. Furthermore, these networks were integrated with microarray and RNA sequencing data to gain deeper insight into the underlying biology of gene expression differences between MCF-7 and MDA-MB-231 breast cancer cell lines, representing weakly and highly invasive breast carcinomas, respectively. Differential genes up-regulated in the MDA-MB-231 compared to the MCF-7 cell line were found to display enrichment in the gene set originating from the non-canonical network. Moreover, we identified and validated differentially regulated modules representing canonical and non-canonical WNT pathway components specific for the aggressive basal-like breast cancer subtype. CONCLUSIONS: In conclusion, we demonstrated that these newly constructed WNT networks reliably reflect distinct WNT signaling processes. Using transcriptomic data, we shaped these networks into comprehensive modules of the genes implicated in the aggressive basal-like breast cancer subtype and demonstrated that non-canonical WNT signaling is important in this context. The topology of these networks can be further refined in the future by integration with complementary data such as protein-protein interactions, in order to gain greater insight into signaling processes. Public Library of Science 2015-12-03 /pmc/articles/PMC4669165/ /pubmed/26632845 http://dx.doi.org/10.1371/journal.pone.0144014 Text en © 2015 Bayerlová et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bayerlová, Michaela Klemm, Florian Kramer, Frank Pukrop, Tobias Beißbarth, Tim Bleckmann, Annalen Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title | Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title_full | Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title_fullStr | Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title_full_unstemmed | Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title_short | Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data |
title_sort | newly constructed network models of different wnt signaling cascades applied to breast cancer expression data |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669165/ https://www.ncbi.nlm.nih.gov/pubmed/26632845 http://dx.doi.org/10.1371/journal.pone.0144014 |
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