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Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers

Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast ca...

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Autores principales: De, Pradip, Carlson, Jennifer H., Wu, Hui, Marcus, Adam, Leyland-Jones, Brian, Dey, Nandini
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190013/
https://www.ncbi.nlm.nih.gov/pubmed/27281609
http://dx.doi.org/10.18632/oncotarget.8988
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author De, Pradip
Carlson, Jennifer H.
Wu, Hui
Marcus, Adam
Leyland-Jones, Brian
Dey, Nandini
author_facet De, Pradip
Carlson, Jennifer H.
Wu, Hui
Marcus, Adam
Leyland-Jones, Brian
Dey, Nandini
author_sort De, Pradip
collection PubMed
description Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.
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spelling pubmed-51900132017-01-05 Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers De, Pradip Carlson, Jennifer H. Wu, Hui Marcus, Adam Leyland-Jones, Brian Dey, Nandini Oncotarget Research Paper Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronection-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP. Impact Journals LLC 2016-04-26 /pmc/articles/PMC5190013/ /pubmed/27281609 http://dx.doi.org/10.18632/oncotarget.8988 Text en Copyright: © 2016 De et al. http://creativecommons.org/licenses/by/2.5/ 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 credited.
spellingShingle Research Paper
De, Pradip
Carlson, Jennifer H.
Wu, Hui
Marcus, Adam
Leyland-Jones, Brian
Dey, Nandini
Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title_full Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title_fullStr Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title_full_unstemmed Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title_short Wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
title_sort wnt-beta-catenin pathway signals metastasis-associated tumor cell phenotypes in triple negative breast cancers
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190013/
https://www.ncbi.nlm.nih.gov/pubmed/27281609
http://dx.doi.org/10.18632/oncotarget.8988
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