Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis

Autores
Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro Ezequiel; Proietti Anastasi, Cecilia Jazmín; Amasino, Matías Federico; Hong, Tao; Yang, Mei; Liao, Yiji; Chiang, Huai-Chin; Kaklamani, Virginia G.; Jeselsohn, Rinath; Vadlamudi, Ratna K.; Huang, Tim Hui Ming; Li, Rong; De Angelis, Carmine; Fu, Xiaoyong; Elizalde, Patricia Virginia; Schiff, Rachel; Brown, Myles; Xu, Kexin
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within.
Fil: Wu, Yanming. University of Texas at San Antonio; Estados Unidos
Fil: Zhang, Zhao. University of Texas at San Antonio; Estados Unidos
Fil: Cenciarini, Mauro Ezequiel. 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: 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; Argentina
Fil: Amasino, Matías Federico. 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: Hong, Tao. University of Texas at San Antonio; Estados Unidos. Central South University; China
Fil: Yang, Mei. University of Texas at San Antonio; Estados Unidos
Fil: Liao, Yiji. University of Texas at San Antonio; Estados Unidos
Fil: Chiang, Huai-Chin. University of Texas at San Antonio; Estados Unidos. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Kaklamani, Virginia G.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Jeselsohn, Rinath. Dana-farber Cancer Institute; Estados Unidos
Fil: Vadlamudi, Ratna K.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Huang, Tim Hui Ming. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Li, Rong. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: De Angelis, Carmine. Baylor College Of Medicine; Estados Unidos
Fil: Fu, Xiaoyong. Baylor College Of Medicine; Estados Unidos
Fil: 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; Argentina
Fil: Schiff, Rachel. Baylor College Of Medicine; Estados Unidos
Fil: Brown, Myles. Dana farber Cancer Institute; Estados Unidos
Fil: Xu, Kexin. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Materia
EZH2
ERalpha signaling
DNA methylation
Tamoxifen resistance
Epigenetic therapy
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:11336/130301
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/130301
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axisWu, YanmingZhang, ZhaoCenciarini, Mauro EzequielProietti Anastasi, Cecilia JazmínAmasino, Matías FedericoHong, TaoYang, MeiLiao, YijiChiang, Huai-ChinKaklamani, Virginia G.Jeselsohn, RinathVadlamudi, Ratna K.Huang, Tim Hui MingLi, RongDe Angelis, CarmineFu, XiaoyongElizalde, Patricia VirginiaSchiff, RachelBrown, MylesXu, KexinEZH2ERalpha signalingDNA methylationTamoxifen resistanceEpigenetic therapyhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within.Fil: Wu, Yanming. University of Texas at San Antonio; Estados UnidosFil: Zhang, Zhao. University of Texas at San Antonio; Estados UnidosFil: Cenciarini, Mauro Ezequiel. 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: Amasino, Matías Federico. 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: Hong, Tao. University of Texas at San Antonio; Estados Unidos. Central South University; ChinaFil: Yang, Mei. University of Texas at San Antonio; Estados UnidosFil: Liao, Yiji. University of Texas at San Antonio; Estados UnidosFil: Chiang, Huai-Chin. University of Texas at San Antonio; Estados Unidos. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;Fil: Kaklamani, Virginia G.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;Fil: Jeselsohn, Rinath. Dana-farber Cancer Institute; Estados UnidosFil: Vadlamudi, Ratna K.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;Fil: Huang, Tim Hui Ming. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;Fil: Li, Rong. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;Fil: De Angelis, Carmine. Baylor College Of Medicine; Estados UnidosFil: Fu, Xiaoyong. Baylor College Of Medicine; Estados UnidosFil: 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; ArgentinaFil: Schiff, Rachel. Baylor College Of Medicine; Estados UnidosFil: Brown, Myles. Dana farber Cancer Institute; Estados UnidosFil: Xu, Kexin. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;American Association for Cancer Research2018-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/130301Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro Ezequiel; Proietti Anastasi, Cecilia Jazmín; Amasino, Matías Federico; et al.; Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis; American Association for Cancer Research; Cancer Research; 78; 3; 2-2018; 671-6840008-5472CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-17-1327info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/78/3/671info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967248/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-17T11:14:00Zoai:ri.conicet.gov.ar:11336/130301instacron: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:34982025-09-17 11:14:01.108CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
title Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
spellingShingle Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
Wu, Yanming
EZH2
ERalpha signaling
DNA methylation
Tamoxifen resistance
Epigenetic therapy
title_short Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
title_full Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
title_fullStr Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
title_full_unstemmed Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
title_sort Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis
dc.creator.none.fl_str_mv Wu, Yanming
Zhang, Zhao
Cenciarini, Mauro Ezequiel
Proietti Anastasi, Cecilia Jazmín
Amasino, Matías Federico
Hong, Tao
Yang, Mei
Liao, Yiji
Chiang, Huai-Chin
Kaklamani, Virginia G.
Jeselsohn, Rinath
Vadlamudi, Ratna K.
Huang, Tim Hui Ming
Li, Rong
De Angelis, Carmine
Fu, Xiaoyong
Elizalde, Patricia Virginia
Schiff, Rachel
Brown, Myles
Xu, Kexin
author Wu, Yanming
author_facet Wu, Yanming
Zhang, Zhao
Cenciarini, Mauro Ezequiel
Proietti Anastasi, Cecilia Jazmín
Amasino, Matías Federico
Hong, Tao
Yang, Mei
Liao, Yiji
Chiang, Huai-Chin
Kaklamani, Virginia G.
Jeselsohn, Rinath
Vadlamudi, Ratna K.
Huang, Tim Hui Ming
Li, Rong
De Angelis, Carmine
Fu, Xiaoyong
Elizalde, Patricia Virginia
Schiff, Rachel
Brown, Myles
Xu, Kexin
author_role author
author2 Zhang, Zhao
Cenciarini, Mauro Ezequiel
Proietti Anastasi, Cecilia Jazmín
Amasino, Matías Federico
Hong, Tao
Yang, Mei
Liao, Yiji
Chiang, Huai-Chin
Kaklamani, Virginia G.
Jeselsohn, Rinath
Vadlamudi, Ratna K.
Huang, Tim Hui Ming
Li, Rong
De Angelis, Carmine
Fu, Xiaoyong
Elizalde, Patricia Virginia
Schiff, Rachel
Brown, Myles
Xu, Kexin
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EZH2
ERalpha signaling
DNA methylation
Tamoxifen resistance
Epigenetic therapy
topic EZH2
ERalpha signaling
DNA methylation
Tamoxifen resistance
Epigenetic therapy
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within.
Fil: Wu, Yanming. University of Texas at San Antonio; Estados Unidos
Fil: Zhang, Zhao. University of Texas at San Antonio; Estados Unidos
Fil: Cenciarini, Mauro Ezequiel. 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: 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; Argentina
Fil: Amasino, Matías Federico. 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: Hong, Tao. University of Texas at San Antonio; Estados Unidos. Central South University; China
Fil: Yang, Mei. University of Texas at San Antonio; Estados Unidos
Fil: Liao, Yiji. University of Texas at San Antonio; Estados Unidos
Fil: Chiang, Huai-Chin. University of Texas at San Antonio; Estados Unidos. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Kaklamani, Virginia G.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Jeselsohn, Rinath. Dana-farber Cancer Institute; Estados Unidos
Fil: Vadlamudi, Ratna K.. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Huang, Tim Hui Ming. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: Li, Rong. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
Fil: De Angelis, Carmine. Baylor College Of Medicine; Estados Unidos
Fil: Fu, Xiaoyong. Baylor College Of Medicine; Estados Unidos
Fil: 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; Argentina
Fil: Schiff, Rachel. Baylor College Of Medicine; Estados Unidos
Fil: Brown, Myles. Dana farber Cancer Institute; Estados Unidos
Fil: Xu, Kexin. University Of Texas Health Science Center At San Antonio (ut Health San Antonio) ; University Of Texas At San Antonio;
description Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor a (ERa) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERa cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERa coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program. Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within.
publishDate 2018
dc.date.none.fl_str_mv 2018-02
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/11336/130301
Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro Ezequiel; Proietti Anastasi, Cecilia Jazmín; Amasino, Matías Federico; et al.; Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis; American Association for Cancer Research; Cancer Research; 78; 3; 2-2018; 671-684
0008-5472
CONICET Digital
CONICET
url http://hdl.handle.net/11336/130301
identifier_str_mv Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro Ezequiel; Proietti Anastasi, Cecilia Jazmín; Amasino, Matías Federico; et al.; Tamoxifen resistance in breast cancer is regulated by the EZH2–ERa–GREB1 transcriptional axis; American Association for Cancer Research; Cancer Research; 78; 3; 2-2018; 671-684
0008-5472
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-17-1327
info:eu-repo/semantics/altIdentifier/url/https://cancerres.aacrjournals.org/content/78/3/671
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967248/
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
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
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 13.001348

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