Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

Cordo Russo, Rosalia Ines; Béguelin, W.; Díaz Flaqué, María Celeste; Proietti Anastasi, Cecilia Jazmín; Venturutti, Leandro; Galigniana, Natalia Maricel; Tkach, Mercedes; Guzmán, P.; Roa, J.C.; O'Brien, N.A.; Charreau, Eduardo Hernan; Schillaci, Roxana; Elizalde, Patricia Virginia

Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Curren...

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Detalhes bibliográficos
Autores:	Cordo Russo, Rosalia Ines, Béguelin, W., Díaz Flaqué, María Celeste, Proietti Anastasi, Cecilia Jazmín, Venturutti, Leandro, Galigniana, Natalia Maricel, Tkach, Mercedes, Guzmán, P., Roa, J.C., O'Brien, N.A., Charreau, Eduardo Hernan, Schillaci, Roxana, Elizalde, Patricia Virginia
Formato:	artículo
Estado:	Versión publicada
Fecha de publicación:	2015
País:	Argentina
Recursos:	Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:	CONICET Digital (CONICET)
Idioma:	inglés
OAI Identifier:	oai:ri.conicet.gov.ar:11336/102492
Acesso em linha:	http://hdl.handle.net/11336/102492
Access Level:	acceso abierto
Palavra-chave:	NUCLEAR ERBB-2/ERBB-3 DIMERS BREAST CANCER TRASTUZUMAB RESISTANCE HEREGULIN STAT3 https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3

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network_name_str	Argentina
repository_id_str
dc.title.none.fl_str_mv	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
title	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
spellingShingle	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance Cordo Russo, Rosalia Ines NUCLEAR ERBB-2/ERBB-3 DIMERS BREAST CANCER TRASTUZUMAB RESISTANCE HEREGULIN STAT3 https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3
title_short	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
title_full	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
title_fullStr	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
title_full_unstemmed	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
title_sort	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance
dc.creator.none.fl_str_mv	Cordo Russo, Rosalia Ines Béguelin, W. Díaz Flaqué, María Celeste Proietti Anastasi, Cecilia Jazmín Venturutti, Leandro Galigniana, Natalia Maricel Tkach, Mercedes Guzmán, P. Roa, J.C. O'Brien, N.A. Charreau, Eduardo Hernan Schillaci, Roxana Elizalde, Patricia Virginia
author	Cordo Russo, Rosalia Ines
author_facet	Cordo Russo, Rosalia Ines Béguelin, W. Díaz Flaqué, María Celeste Proietti Anastasi, Cecilia Jazmín Venturutti, Leandro Galigniana, Natalia Maricel Tkach, Mercedes Guzmán, P. Roa, J.C. O'Brien, N.A. Charreau, Eduardo Hernan Schillaci, Roxana Elizalde, Patricia Virginia
author_role	author
author2	Béguelin, W. Díaz Flaqué, María Celeste Proietti Anastasi, Cecilia Jazmín Venturutti, Leandro Galigniana, Natalia Maricel Tkach, Mercedes Guzmán, P. Roa, J.C. O'Brien, N.A. Charreau, Eduardo Hernan Schillaci, Roxana Elizalde, Patricia Virginia
author2_role	author author author author author author author author author author author author
dc.subject.none.fl_str_mv	NUCLEAR ERBB-2/ERBB-3 DIMERS BREAST CANCER TRASTUZUMAB RESISTANCE HEREGULIN STAT3 https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3
topic	NUCLEAR ERBB-2/ERBB-3 DIMERS BREAST CANCER TRASTUZUMAB RESISTANCE HEREGULIN STAT3 https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3
description	Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.
publishDate	2015
dc.date.none.fl_str_mv	2015-06
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/11336/102492 Cordo Russo, Rosalia Ines; Béguelin, W.; Díaz Flaqué, María Celeste; Proietti Anastasi, Cecilia Jazmín; Venturutti, Leandro; et al.; Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance; Nature Publishing Group; Oncogene; 34; 6-2015; 3413-3428 0950-9232 CONICET Digital CONICET
url	http://hdl.handle.net/11336/102492
identifier_str_mv	Cordo Russo, Rosalia Ines; Béguelin, W.; Díaz Flaqué, María Celeste; Proietti Anastasi, Cecilia Jazmín; Venturutti, Leandro; et al.; Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance; Nature Publishing Group; Oncogene; 34; 6-2015; 3413-3428 0950-9232 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/onc2014272 info:eu-repo/semantics/altIdentifier/doi/10.1038/onc.2014.272
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv	application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf
dc.publisher.none.fl_str_mv	Nature Publishing Group
publisher.none.fl_str_mv	Nature Publishing Group
dc.source.none.fl_str_mv	reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str	Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str	CONICET Digital (CONICET)
collection	CONICET Digital (CONICET)
repository.name.fl_str_mv	CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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spelling	Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistanceCordo Russo, Rosalia InesBéguelin, W.Díaz Flaqué, María CelesteProietti Anastasi, Cecilia JazmínVenturutti, LeandroGaligniana, Natalia MaricelTkach, MercedesGuzmán, P.Roa, J.C.O'Brien, N.A.Charreau, Eduardo HernanSchillaci, RoxanaElizalde, Patricia VirginiaNUCLEAR ERBB-2/ERBB-3 DIMERSBREAST CANCERTRASTUZUMAB RESISTANCEHEREGULINSTAT3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.Fil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Béguelin, W.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Natalia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guzmán, P.. Universidad de La Frontera; ChileFil: Roa, J.C.. Universidad de La Frontera; ChileFil: O'Brien, N.A.. David Geffen School of Medicine at UCLA; Estados UnidosFil: Charreau, Eduardo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaNature Publishing Group2015-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/102492Cordo Russo, Rosalia Ines; Béguelin, W.; Díaz Flaqué, María Celeste; Proietti Anastasi, Cecilia Jazmín; Venturutti, Leandro; et al.; Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance; Nature Publishing Group; Oncogene; 34; 6-2015; 3413-34280950-9232CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/onc2014272info:eu-repo/semantics/altIdentifier/doi/10.1038/onc.2014.272info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:42:11Zoai:ri.conicet.gov.ar:11336/102492instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982024-05-08 13:42:11.771CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

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