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Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression

Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism o...

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Autores principales: Gracanin, Ana, Timmermans-Sprang, Elpetra P. M., van Wolferen, Monique E., Rao, Nagesha A. S., Grizelj, Juraj, Vince, Silvijo, Hellmen, Eva, Mol, Jan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041801/
https://www.ncbi.nlm.nih.gov/pubmed/24887235
http://dx.doi.org/10.1371/journal.pone.0098698
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author Gracanin, Ana
Timmermans-Sprang, Elpetra P. M.
van Wolferen, Monique E.
Rao, Nagesha A. S.
Grizelj, Juraj
Vince, Silvijo
Hellmen, Eva
Mol, Jan A.
author_facet Gracanin, Ana
Timmermans-Sprang, Elpetra P. M.
van Wolferen, Monique E.
Rao, Nagesha A. S.
Grizelj, Juraj
Vince, Silvijo
Hellmen, Eva
Mol, Jan A.
author_sort Gracanin, Ana
collection PubMed
description Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1) and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand–independent mechanisms.
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spelling pubmed-40418012014-06-09 Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression Gracanin, Ana Timmermans-Sprang, Elpetra P. M. van Wolferen, Monique E. Rao, Nagesha A. S. Grizelj, Juraj Vince, Silvijo Hellmen, Eva Mol, Jan A. PLoS One Research Article Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1) and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand–independent mechanisms. Public Library of Science 2014-06-02 /pmc/articles/PMC4041801/ /pubmed/24887235 http://dx.doi.org/10.1371/journal.pone.0098698 Text en © 2014 Gracanin 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
Gracanin, Ana
Timmermans-Sprang, Elpetra P. M.
van Wolferen, Monique E.
Rao, Nagesha A. S.
Grizelj, Juraj
Vince, Silvijo
Hellmen, Eva
Mol, Jan A.
Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title_full Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title_fullStr Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title_full_unstemmed Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title_short Ligand-Independent Canonical Wnt Activity in Canine Mammary Tumor Cell Lines Associated with Aberrant LEF1 Expression
title_sort ligand-independent canonical wnt activity in canine mammary tumor cell lines associated with aberrant lef1 expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041801/
https://www.ncbi.nlm.nih.gov/pubmed/24887235
http://dx.doi.org/10.1371/journal.pone.0098698
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