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Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β

Mammary tumorigenesis and epithelial–mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis,...

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Autores principales: Parvani, Jenny G., Galliher-Beckley, Amy J., Schiemann, Barbara J., Schiemann, William P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814150/
https://www.ncbi.nlm.nih.gov/pubmed/24006485
http://dx.doi.org/10.1091/mbc.E12-10-0776
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author Parvani, Jenny G.
Galliher-Beckley, Amy J.
Schiemann, Barbara J.
Schiemann, William P.
author_facet Parvani, Jenny G.
Galliher-Beckley, Amy J.
Schiemann, Barbara J.
Schiemann, William P.
author_sort Parvani, Jenny G.
collection PubMed
description Mammary tumorigenesis and epithelial–mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin–deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin–specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.
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spelling pubmed-38141502014-01-16 Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β Parvani, Jenny G. Galliher-Beckley, Amy J. Schiemann, Barbara J. Schiemann, William P. Mol Biol Cell Articles Mammary tumorigenesis and epithelial–mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin–deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin–specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients. The American Society for Cell Biology 2013-11-01 /pmc/articles/PMC3814150/ /pubmed/24006485 http://dx.doi.org/10.1091/mbc.E12-10-0776 Text en © 2013 Parvani 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
Parvani, Jenny G.
Galliher-Beckley, Amy J.
Schiemann, Barbara J.
Schiemann, William P.
Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title_full Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title_fullStr Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title_full_unstemmed Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title_short Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β
title_sort targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by tgf-β
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814150/
https://www.ncbi.nlm.nih.gov/pubmed/24006485
http://dx.doi.org/10.1091/mbc.E12-10-0776
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