Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells

Autores
Shortrede, Jorge Eduardo; Uzair, Ivonne Denise; Neira, Flavia Judith; Flamini, Marina Ines; Sanchez, Angel Matias
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment.
Fil: Shortrede, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Uzair, Ivonne Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Neira, Flavia Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Materia
Breast Cancer Metastasis
Estrogen
N-Wasp
Paxillin
Raloxifene
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:11336/49782
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/49782
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cellsShortrede, Jorge EduardoUzair, Ivonne DeniseNeira, Flavia JudithFlamini, Marina InesSanchez, Angel MatiasBreast Cancer MetastasisEstrogenN-WaspPaxillinRaloxifenehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment.Fil: Shortrede, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Uzair, Ivonne Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Neira, Flavia Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaElsevier Ireland2016-07-15info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/49782Shortrede, Jorge Eduardo; Uzair, Ivonne Denise; Neira, Flavia Judith; Flamini, Marina Ines; Sanchez, Angel Matias; Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells; Elsevier Ireland; Molecular and Cellular Endocrinology; 430; 15-7-2016; 56-670303-7207CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.mce.2016.04.007info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0303720716301125info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:43:36Zoai:ri.conicet.gov.ar:11336/49782instacron: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 09:43:36.818CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
title Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
spellingShingle Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
Shortrede, Jorge Eduardo
Breast Cancer Metastasis
Estrogen
N-Wasp
Paxillin
Raloxifene
title_short Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
title_full Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
title_fullStr Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
title_full_unstemmed Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
title_sort Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells
dc.creator.none.fl_str_mv Shortrede, Jorge Eduardo
Uzair, Ivonne Denise
Neira, Flavia Judith
Flamini, Marina Ines
Sanchez, Angel Matias
author Shortrede, Jorge Eduardo
author_facet Shortrede, Jorge Eduardo
Uzair, Ivonne Denise
Neira, Flavia Judith
Flamini, Marina Ines
Sanchez, Angel Matias
author_role author
author2 Uzair, Ivonne Denise
Neira, Flavia Judith
Flamini, Marina Ines
Sanchez, Angel Matias
author2_role author
author
author
author
dc.subject.none.fl_str_mv Breast Cancer Metastasis
Estrogen
N-Wasp
Paxillin
Raloxifene
topic Breast Cancer Metastasis
Estrogen
N-Wasp
Paxillin
Raloxifene
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment.
Fil: Shortrede, Jorge Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Uzair, Ivonne Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Neira, Flavia Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
description Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment.
publishDate 2016
dc.date.none.fl_str_mv 2016-07-15
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/11336/49782
Shortrede, Jorge Eduardo; Uzair, Ivonne Denise; Neira, Flavia Judith; Flamini, Marina Ines; Sanchez, Angel Matias; Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells; Elsevier Ireland; Molecular and Cellular Endocrinology; 430; 15-7-2016; 56-67
0303-7207
CONICET Digital
CONICET
url http://hdl.handle.net/11336/49782
identifier_str_mv Shortrede, Jorge Eduardo; Uzair, Ivonne Denise; Neira, Flavia Judith; Flamini, Marina Ines; Sanchez, Angel Matias; Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells; Elsevier Ireland; Molecular and Cellular Endocrinology; 430; 15-7-2016; 56-67
0303-7207
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.mce.2016.04.007
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0303720716301125
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
dc.publisher.none.fl_str_mv Elsevier Ireland
publisher.none.fl_str_mv Elsevier Ireland
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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score 13.070432

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