Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells

Autores
Espinoza, Ingrid; Yang, Lin; Steen, Travis Vander; Vellón, Luciano; Cuyàs, Elisabet; Verdura, Sara; Lau, Lester; Menendez, Javier A.; Lupu, Ruth
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptorα6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistancephenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we tookadvantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine theintegrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role ofCCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with asingle amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistancephenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM,which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement foranchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assaysrevealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability ofrecombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotypethat involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells.
Fil: Espinoza, Ingrid. University of Mississippi; Estados Unidos
Fil: Yang, Lin. Mayo Clinic ; Estados Unidos
Fil: Steen, Travis Vander. Mayo Clinic ; Estados Unidos
Fil: Vellón, Luciano. 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; Argentina
Fil: Cuyàs, Elisabet. No especifíca;
Fil: Verdura, Sara. No especifíca;
Fil: Lau, Lester. University of Illinois; Estados Unidos
Fil: Menendez, Javier A.. No especifíca;
Fil: Lupu, Ruth. No especifíca;
Materia
CYR61
ESTROGEN RECEPTOR
INTEGRINS
MATRICELLULAR PROTEINS
TAMOXIFEN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/218260

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oai_identifier_str oai:ri.conicet.gov.ar:11336/218260
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cellsEspinoza, IngridYang, LinSteen, Travis VanderVellón, LucianoCuyàs, ElisabetVerdura, SaraLau, LesterMenendez, Javier A.Lupu, RuthCYR61ESTROGEN RECEPTORINTEGRINSMATRICELLULAR PROTEINSTAMOXIFENhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptorα6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistancephenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we tookadvantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine theintegrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role ofCCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with asingle amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistancephenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM,which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement foranchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assaysrevealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability ofrecombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotypethat involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells.Fil: Espinoza, Ingrid. University of Mississippi; Estados UnidosFil: Yang, Lin. Mayo Clinic ; Estados UnidosFil: Steen, Travis Vander. Mayo Clinic ; Estados UnidosFil: Vellón, Luciano. 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: Cuyàs, Elisabet. No especifíca;Fil: Verdura, Sara. No especifíca;Fil: Lau, Lester. University of Illinois; Estados UnidosFil: Menendez, Javier A.. No especifíca;Fil: Lupu, Ruth. No especifíca;Impact Journals2022-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/218260Espinoza, Ingrid; Yang, Lin; Steen, Travis Vander; Vellón, Luciano; Cuyàs, Elisabet; et al.; Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells; Impact Journals; Aging; 14; 3; 2-2022; 1200-12131945-4589CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.18632/aging.203882info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:08:33Zoai:ri.conicet.gov.ar:11336/218260instacron: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:34982025-09-29 10:08:33.911CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
title Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
spellingShingle Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
Espinoza, Ingrid
CYR61
ESTROGEN RECEPTOR
INTEGRINS
MATRICELLULAR PROTEINS
TAMOXIFEN
title_short Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
title_full Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
title_fullStr Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
title_full_unstemmed Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
title_sort Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells
dc.creator.none.fl_str_mv Espinoza, Ingrid
Yang, Lin
Steen, Travis Vander
Vellón, Luciano
Cuyàs, Elisabet
Verdura, Sara
Lau, Lester
Menendez, Javier A.
Lupu, Ruth
author Espinoza, Ingrid
author_facet Espinoza, Ingrid
Yang, Lin
Steen, Travis Vander
Vellón, Luciano
Cuyàs, Elisabet
Verdura, Sara
Lau, Lester
Menendez, Javier A.
Lupu, Ruth
author_role author
author2 Yang, Lin
Steen, Travis Vander
Vellón, Luciano
Cuyàs, Elisabet
Verdura, Sara
Lau, Lester
Menendez, Javier A.
Lupu, Ruth
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CYR61
ESTROGEN RECEPTOR
INTEGRINS
MATRICELLULAR PROTEINS
TAMOXIFEN
topic CYR61
ESTROGEN RECEPTOR
INTEGRINS
MATRICELLULAR PROTEINS
TAMOXIFEN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptorα6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistancephenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we tookadvantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine theintegrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role ofCCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with asingle amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistancephenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM,which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement foranchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assaysrevealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability ofrecombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotypethat involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells.
Fil: Espinoza, Ingrid. University of Mississippi; Estados Unidos
Fil: Yang, Lin. Mayo Clinic ; Estados Unidos
Fil: Steen, Travis Vander. Mayo Clinic ; Estados Unidos
Fil: Vellón, Luciano. 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; Argentina
Fil: Cuyàs, Elisabet. No especifíca;
Fil: Verdura, Sara. No especifíca;
Fil: Lau, Lester. University of Illinois; Estados Unidos
Fil: Menendez, Javier A.. No especifíca;
Fil: Lupu, Ruth. No especifíca;
description CCN1/CYR61 promotes angiogenesis, tumor growth and chemoresistance by binding to its integrin receptor αvβ3 in endothelial and breast cancer (BC) cells. CCN1 controls also tissue regeneration by engaging its integrin receptorα6β1 to induce fibroblast senescence. Here, we explored if the ability of CCN1 to drive an endocrine resistancephenotype in estrogen receptor-positive BC cells relies on interactions with either αvβ3 or α6β1. First, we tookadvantage of site-specific mutagenesis abolishing the CCN1 receptor-binding sites to αvβ3 and α6β1 to determine theintegrin partner responsible for CCN1-driven endocrine resistance. Second, we explored a putative nuclear role ofCCN1 in regulating ERα-driven transcriptional responses. Retroviral forced expression of a CCN1 derivative with asingle amino acid change (D125A) that abrogates binding to αvβ3 partially phenocopied the endocrine resistancephenotype induced upon overexpression of wild-type (WT) CCN1. Forced expression of the CCN1 mutant TM,which abrogates all the T1, H1, and H2 binding sites to α6β1, failed to bypass the estrogen requirement foranchorage-independent growth or to promote resistance to tamoxifen. Wild-type CCN1 promoted estradiol-independent transcriptional activity of ERα and enhanced ERα agonist response to tamoxifen. The α6β1-binding-defective TM-CCN1 mutant lost the ERα co-activator-like behavior of WT-CCN1. Co-immunoprecipitation assaysrevealed a direct interaction between endogenous CCN1 and ERα, and in vitro approaches confirmed the ability ofrecombinant CCN1 to bind ERα. CCN1 signaling via α6β1, but not via αvβ3, drives an endocrine resistance phenotypethat involves a direct binding of CCN1 to ERα to regulate itstranscriptional activity in ER+ BC cells.
publishDate 2022
dc.date.none.fl_str_mv 2022-02
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/11336/218260
Espinoza, Ingrid; Yang, Lin; Steen, Travis Vander; Vellón, Luciano; Cuyàs, Elisabet; et al.; Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells; Impact Journals; Aging; 14; 3; 2-2022; 1200-1213
1945-4589
CONICET Digital
CONICET
url http://hdl.handle.net/11336/218260
identifier_str_mv Espinoza, Ingrid; Yang, Lin; Steen, Travis Vander; Vellón, Luciano; Cuyàs, Elisabet; et al.; Binding of the angiogenic/senescence inducer CCN1/CYR61 to integrin α6β1 drives endocrine resistance in breast cancer cells; Impact Journals; Aging; 14; 3; 2-2022; 1200-1213
1945-4589
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.18632/aging.203882
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
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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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