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Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer
Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-β (TGF-β) and EMT preceded breast cancer outgrowth in three-dimensio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135469/ https://www.ncbi.nlm.nih.gov/pubmed/21613543 http://dx.doi.org/10.1091/mbc.E11-04-0306 |
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author | Wendt, Michael K. Taylor, Molly A. Schiemann, Barbara J. Schiemann, William P. |
author_facet | Wendt, Michael K. Taylor, Molly A. Schiemann, Barbara J. Schiemann, William P. |
author_sort | Wendt, Michael K. |
collection | PubMed |
description | Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-β (TGF-β) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D-cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-β. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re-express E-cad formed branched organoids, down-regulated β1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating β1 integrin expression necessary for metastatic outgrowth. |
format | Online Article Text |
id | pubmed-3135469 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-31354692011-09-30 Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer Wendt, Michael K. Taylor, Molly A. Schiemann, Barbara J. Schiemann, William P. Mol Biol Cell Articles Reduced epithelial cadherin (E-cad) is a hallmark of invasive carcinomas that have acquired epithelial-mesenchymal transition (EMT) phenotypes. Here we show that down-regulated E-cad expression induced by transforming growth factor-β (TGF-β) and EMT preceded breast cancer outgrowth in three-dimensional (3D) organotypic assays and in the lungs of mice. Pharmacological inhibitors against focal adhesion kinase prevented metastatic outgrowth of newly seeded organoids, but not that of their fully established counterparts. Interrogating the D2-HAN (hyperplastic alveolar nodule) model of breast cancer dormancy and metastasis showed that dormant D2.OR cells produced branched organoid morphologies in 3D-cultures, and expressed robust quantities of E-cad that was uncoupled from regulation by TGF-β. In contrast, metastatic D2.A1 organoids were spherical and wholly lacked E-cad expression. Interestingly, D2.A1 cells engineered to re-express E-cad formed branched organoids, down-regulated β1 integrin expression, and failed to undergo metastatic outgrowth. The tumor-suppressing function of E-cad was inactivated by increased microenvironmental rigidity, and was not recapitulated by expression of an E-cad mutant lacking its extracellular domain. Twist expression, but not that of Snail, reinitiated metastatic outgrowth in dormant D2.OR cells. Our findings show that EMT and its down-regulated expression of E-cad circumvent breast cancer dormancy in part by facilitating β1 integrin expression necessary for metastatic outgrowth. The American Society for Cell Biology 2011-07-15 /pmc/articles/PMC3135469/ /pubmed/21613543 http://dx.doi.org/10.1091/mbc.E11-04-0306 Text en © 2011 Wendt et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Wendt, Michael K. Taylor, Molly A. Schiemann, Barbara J. Schiemann, William P. Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title | Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title_full | Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title_fullStr | Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title_full_unstemmed | Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title_short | Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
title_sort | down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135469/ https://www.ncbi.nlm.nih.gov/pubmed/21613543 http://dx.doi.org/10.1091/mbc.E11-04-0306 |
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