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dc.contributor.author
Menendez, Javier
dc.contributor.author
Schroeder, Barbara
dc.contributor.author
Peirce, Susan K.
dc.contributor.author
Vellón, Luciano
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Papadimitropoulou, Adriana
dc.contributor.author
Espinoza, Ingrid
dc.contributor.author
Lupu, Ruth
dc.date.available
2015-12-18T18:44:57Z
dc.date.issued
2015-04-17
dc.identifier.citation
Menendez, Javier; Schroeder, Barbara; Peirce, Susan K.; Vellón, Luciano; Papadimitropoulou, Adriana; et al.; Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling; Oxford Univ Press Inc; Journal Of The National Cancer Institute.; 107; 6; 17-4-2015; 1-11
dc.identifier.issn
0027-8874
dc.identifier.uri
http://hdl.handle.net/11336/3060
dc.description.abstract
Background: Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2?s extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective. Methods: To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student?s t test were used to analyze differences. All statistical tests were two-sided. Results: The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451?466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage- independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451?466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested. Conclusions: These findings reveal that an essential ?activating? sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford Univ Press Inc
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Breast Carcinomas
dc.subject
Her2
dc.subject
Herceptin
dc.subject.classification
Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-03-30 10:35:44.97925-03
dc.identifier.eissn
1460-2105
dc.journal.volume
107
dc.journal.number
6
dc.journal.pagination
1-11
dc.journal.pais
Reino Unido
dc.journal.ciudad
Oxford
dc.description.fil
Fil: Menendez, Javier. Instituto Catalán de Oncología; España
dc.description.fil
Fil: Schroeder, Barbara. Mayo Clinic Cancer Center; Estados Unidos
dc.description.fil
Fil: Peirce, Susan K.. Kateric CROC; Estados Unidos
dc.description.fil
Fil: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
dc.description.fil
Fil: Papadimitropoulou, Adriana. Laboratory of Molecular Biology and Immunobiotechnology. Hellenic Pasteur Institute; Estados Unidos
dc.description.fil
Fil: Espinoza, Ingrid. Cancer Institute. University of Mississippi Medical Center; Estados Unidos
dc.description.fil
Fil: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos
dc.journal.title
Journal Of The National Cancer Institute.
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://jnci.oxfordjournals.org/content/107/6/djv090.abstract
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/doi:10.1093/jnci/djv090
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