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The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells

Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 k...

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Autores principales: Huang, Wei, Martin, Emily E., Burman, Boris, Gonzalez, Maria E., Kleer, Celina G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041896/
https://www.ncbi.nlm.nih.gov/pubmed/26933820
http://dx.doi.org/10.18632/oncotarget.7734
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author Huang, Wei
Martin, Emily E.
Burman, Boris
Gonzalez, Maria E.
Kleer, Celina G.
author_facet Huang, Wei
Martin, Emily E.
Burman, Boris
Gonzalez, Maria E.
Kleer, Celina G.
author_sort Huang, Wei
collection PubMed
description Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism.
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spelling pubmed-50418962016-10-10 The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells Huang, Wei Martin, Emily E. Burman, Boris Gonzalez, Maria E. Kleer, Celina G. Oncotarget Research Paper Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism. Impact Journals LLC 2016-02-25 /pmc/articles/PMC5041896/ /pubmed/26933820 http://dx.doi.org/10.18632/oncotarget.7734 Text en Copyright: © 2016 Huang 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
Huang, Wei
Martin, Emily E.
Burman, Boris
Gonzalez, Maria E.
Kleer, Celina G.
The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title_full The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title_fullStr The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title_full_unstemmed The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title_short The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells
title_sort matricellular protein ccn6 (wisp3) decreases notch1 and suppresses breast cancer initiating cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041896/
https://www.ncbi.nlm.nih.gov/pubmed/26933820
http://dx.doi.org/10.18632/oncotarget.7734
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