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...
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| Veröffentlicht in: | PloS one 2012-07, Vol.7 (7), p.e41170-e41170 |
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| creator | Le, Xiao-Feng Almeida, Maria I Mao, Weiqun Spizzo, Riccardo Rossi, Simona Nicoloso, Milena S Zhang, Shu Wu, Yun Calin, George A Bast, Jr, Robert C |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0041170 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0041170</identifier><identifier>PMID: 22829924</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated Regions - genetics ; Angiogenesis ; Animals ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Apoptosis ; Biology ; Biopsy ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Cancer ; Cancer metastasis ; Cell adhesion & migration ; Cell culture ; Cell cycle ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Movement - genetics ; Cell proliferation ; Cell Proliferation - drug effects ; Chemotherapy ; Cytoskeleton ; ErbB-2 protein ; Female ; Flow Cytometry ; Gene expression ; Health sciences ; Humans ; Immunoblotting ; Immunotherapy ; Inhibition ; Kinases ; Liver cancer ; Luciferase ; Medicine ; Metastasis ; Mice ; Mice, Nude ; MicroRNA ; MicroRNAs ; MicroRNAs - drug effects ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Monoclonal antibodies ; Penicillin ; Receptor, ErbB-2 - antagonists & inhibitors ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleic acid ; RNA ; Stem cells ; Talin - genetics ; Talin - metabolism ; Targeted cancer therapy ; Trastuzumab ; Xenografts</subject><ispartof>PloS one, 2012-07, Vol.7 (7), p.e41170-e41170</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Le et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Le et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c783t-6546ebc851786a0edd1e18ae05592de3c23728829778709f25637ece84b71dd13</citedby><cites>FETCH-LOGICAL-c783t-6546ebc851786a0edd1e18ae05592de3c23728829778709f25637ece84b71dd13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400637/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400637/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22829924$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tan, Ming</contributor><creatorcontrib>Le, Xiao-Feng</creatorcontrib><creatorcontrib>Almeida, Maria I</creatorcontrib><creatorcontrib>Mao, Weiqun</creatorcontrib><creatorcontrib>Spizzo, Riccardo</creatorcontrib><creatorcontrib>Rossi, Simona</creatorcontrib><creatorcontrib>Nicoloso, Milena S</creatorcontrib><creatorcontrib>Zhang, Shu</creatorcontrib><creatorcontrib>Wu, Yun</creatorcontrib><creatorcontrib>Calin, George A</creatorcontrib><creatorcontrib>Bast, Jr, Robert C</creatorcontrib><title>Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>3' Untranslated Regions - genetics</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Biopsy</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Cell adhesion & migration</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - genetics</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>Cytoskeleton</subject><subject>ErbB-2 protein</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunotherapy</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Luciferase</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - drug effects</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>Monoclonal antibodies</subject><subject>Penicillin</subject><subject>Receptor, ErbB-2 - antagonists & inhibitors</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Stem cells</subject><subject>Talin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Le, Xiao-Feng</au><au>Almeida, Maria I</au><au>Mao, Weiqun</au><au>Spizzo, Riccardo</au><au>Rossi, Simona</au><au>Nicoloso, Milena S</au><au>Zhang, Shu</au><au>Wu, Yun</au><au>Calin, George A</au><au>Bast, Jr, Robert C</au><au>Tan, Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-07-19</date><risdate>2012</risdate><volume>7</volume><issue>7</issue><spage>e41170</spage><epage>e41170</epage><pages>e41170-e41170</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22829924</pmid><doi>10.1371/journal.pone.0041170</doi><tpages>e41170</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-07, Vol.7 (7), p.e41170-e41170 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326223751 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3' Untranslated Regions - genetics Angiogenesis Animals Antibodies, Monoclonal, Humanized - pharmacology Antibodies, Monoclonal, Humanized - therapeutic use Apoptosis Biology Biopsy Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Cancer Cancer metastasis Cell adhesion & migration Cell culture Cell cycle Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Movement - genetics Cell proliferation Cell Proliferation - drug effects Chemotherapy Cytoskeleton ErbB-2 protein Female Flow Cytometry Gene expression Health sciences Humans Immunoblotting Immunotherapy Inhibition Kinases Liver cancer Luciferase Medicine Metastasis Mice Mice, Nude MicroRNA MicroRNAs MicroRNAs - drug effects MicroRNAs - genetics MicroRNAs - metabolism miRNA Monoclonal antibodies Penicillin Receptor, ErbB-2 - antagonists & inhibitors Reverse Transcriptase Polymerase Chain Reaction Ribonucleic acid RNA Stem cells Talin - genetics Talin - metabolism Targeted cancer therapy Trastuzumab Xenografts |
| title | Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer |
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