Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells

Autores
Gonzalez, N.; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pifano, Marina; Alonso, Daniel Fernando; Gomez, D. E.; Lorenzano Menna, Pablo
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success,development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signalingpathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of themost important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhancedactivity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not onlyshowed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but alsoshowed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype.We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylationlevels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, weevaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells.1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreasedestrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrinetherapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition ofRac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
Fil: Gonzalez, N.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Segatori, Valeria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Pifano, Marina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Gomez, D. E.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Small Gtpases
Protein Kinase
Estrogen Receptor
Hormone-Independence
Breast Cancer
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:11336/40554
Acceder
id CONICETDig_3f4a2b58bfef0543f380f44943f6cddd
oai_identifier_str oai:ri.conicet.gov.ar:11336/40554
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cellsGonzalez, N.Cardama, Georgina AlexandraComin, Maria JulietaSegatori, Valeria InésPifano, MarinaAlonso, Daniel FernandoGomez, D. E.Lorenzano Menna, PabloSmall GtpasesProtein KinaseEstrogen ReceptorHormone-IndependenceBreast Cancerhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success,development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signalingpathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of themost important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhancedactivity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not onlyshowed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but alsoshowed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype.We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylationlevels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, weevaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells.1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreasedestrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrinetherapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition ofRac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.Fil: Gonzalez, N.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Segatori, Valeria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Pifano, Marina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Gomez, D. E.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaElsevier Science Inc2017-01info: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/11336/40554Gonzalez, N.; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pifano, Marina; et al.; Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells; Elsevier Science Inc; Cellular Signalling; 30; 1-2017; 154-1610898-6568CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0898656816302947info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cellsig.2016.12.002info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:43:32Zoai:ri.conicet.gov.ar:11336/40554instacron: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:34982025-09-03 09:43:32.302CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
title Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
spellingShingle Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
Gonzalez, N.
Small Gtpases
Protein Kinase
Estrogen Receptor
Hormone-Independence
Breast Cancer
title_short Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
title_full Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
title_fullStr Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
title_full_unstemmed Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
title_sort Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
dc.creator.none.fl_str_mv Gonzalez, N.
Cardama, Georgina Alexandra
Comin, Maria Julieta
Segatori, Valeria Inés
Pifano, Marina
Alonso, Daniel Fernando
Gomez, D. E.
Lorenzano Menna, Pablo
author Gonzalez, N.
author_facet Gonzalez, N.
Cardama, Georgina Alexandra
Comin, Maria Julieta
Segatori, Valeria Inés
Pifano, Marina
Alonso, Daniel Fernando
Gomez, D. E.
Lorenzano Menna, Pablo
author_role author
author2 Cardama, Georgina Alexandra
Comin, Maria Julieta
Segatori, Valeria Inés
Pifano, Marina
Alonso, Daniel Fernando
Gomez, D. E.
Lorenzano Menna, Pablo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Small Gtpases
Protein Kinase
Estrogen Receptor
Hormone-Independence
Breast Cancer
topic Small Gtpases
Protein Kinase
Estrogen Receptor
Hormone-Independence
Breast Cancer
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success,development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signalingpathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of themost important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhancedactivity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not onlyshowed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but alsoshowed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype.We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylationlevels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, weevaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells.1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreasedestrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrinetherapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition ofRac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
Fil: Gonzalez, N.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina
Fil: Segatori, Valeria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Pifano, Marina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Gomez, D. E.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success,development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signalingpathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of themost important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhancedactivity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not onlyshowed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but alsoshowed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype.We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylationlevels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, weevaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells.1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreasedestrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrinetherapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition ofRac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
publishDate 2017
dc.date.none.fl_str_mv 2017-01
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/11336/40554
Gonzalez, N.; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pifano, Marina; et al.; Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells; Elsevier Science Inc; Cellular Signalling; 30; 1-2017; 154-161
0898-6568
CONICET Digital
CONICET
url http://hdl.handle.net/11336/40554
identifier_str_mv Gonzalez, N.; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pifano, Marina; et al.; Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells; Elsevier Science Inc; Cellular Signalling; 30; 1-2017; 154-161
0898-6568
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.sciencedirect.com/science/article/pii/S0898656816302947
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cellsig.2016.12.002
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 Science Inc
publisher.none.fl_str_mv Elsevier Science Inc
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 13.13397

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