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Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer
Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been invest...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400637/ https://www.ncbi.nlm.nih.gov/pubmed/22829924 http://dx.doi.org/10.1371/journal.pone.0041170 |
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author | Le, Xiao-Feng Almeida, Maria I. Mao, Weiqun Spizzo, Riccardo Rossi, Simona Nicoloso, Milena S. Zhang, Shu Wu, Yun Calin, George A. Bast, Robert C. |
author_facet | Le, Xiao-Feng Almeida, Maria I. Mao, Weiqun Spizzo, Riccardo Rossi, Simona Nicoloso, Milena S. Zhang, Shu Wu, Yun Calin, George A. Bast, Robert C. |
author_sort | Le, Xiao-Feng |
collection | PubMed |
description | Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3′-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells. |
format | Online Article Text |
id | pubmed-3400637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34006372012-07-24 Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer Le, Xiao-Feng Almeida, Maria I. Mao, Weiqun Spizzo, Riccardo Rossi, Simona Nicoloso, Milena S. Zhang, Shu Wu, Yun Calin, George A. Bast, Robert C. PLoS One Research Article Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3′-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells. Public Library of Science 2012-07-19 /pmc/articles/PMC3400637/ /pubmed/22829924 http://dx.doi.org/10.1371/journal.pone.0041170 Text en Le 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 Le, Xiao-Feng Almeida, Maria I. Mao, Weiqun Spizzo, Riccardo Rossi, Simona Nicoloso, Milena S. Zhang, Shu Wu, Yun Calin, George A. Bast, Robert C. Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title | Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title_full | Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title_fullStr | Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title_full_unstemmed | Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title_short | Modulation of MicroRNA-194 and Cell Migration by HER2-Targeting Trastuzumab in Breast Cancer |
title_sort | modulation of microrna-194 and cell migration by her2-targeting trastuzumab in breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400637/ https://www.ncbi.nlm.nih.gov/pubmed/22829924 http://dx.doi.org/10.1371/journal.pone.0041170 |
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