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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/218260
Ver los metadatos del registro completo
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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 |
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CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
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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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13.070432 |