Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer

Autores
Menendez, Javier A.; Mehmi, Inderjit; Papadimitropoulou, Adriana; Steen, Travis Vander; Cuyàs, Elisabet; Verdura, Sara; Espinoza, Ingrid; Vellón, Luciano; Atlas, Ella; Lupu, Ruth
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2-breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.
Fil: Menendez, Javier A.. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; España
Fil: Mehmi, Inderjit. The Angeles Clinic And Research Institute; Estados Unidos
Fil: Papadimitropoulou, Adriana. Academy of Athens; Grecia
Fil: Steen, Travis Vander. Mayo Clinic; Estados Unidos
Fil: Cuyàs, Elisabet. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; España
Fil: Verdura, Sara. Institut Català d'Oncologia ; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España
Fil: Espinoza, Ingrid. University of Mississippi; 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: Atlas, Ella. University of Ottawa; Canadá
Fil: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos. Mayo Clinic; Estados Unidos. Academy of Athens; Grecia
Materia
ENDOCRINE RESISTANCE
FULVESTRANT
LUMINAL
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:11336/132522
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/132522
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancerMenendez, Javier A.Mehmi, InderjitPapadimitropoulou, AdrianaSteen, Travis VanderCuyàs, ElisabetVerdura, SaraEspinoza, IngridVellón, LucianoAtlas, EllaLupu, RuthENDOCRINE RESISTANCEFULVESTRANTLUMINALTAMOXIFENhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2-breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.Fil: Menendez, Javier A.. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; EspañaFil: Mehmi, Inderjit. The Angeles Clinic And Research Institute; Estados UnidosFil: Papadimitropoulou, Adriana. Academy of Athens; GreciaFil: Steen, Travis Vander. Mayo Clinic; Estados UnidosFil: Cuyàs, Elisabet. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; EspañaFil: Verdura, Sara. Institut Català d'Oncologia ; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; EspañaFil: Espinoza, Ingrid. University of Mississippi; 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: Atlas, Ella. University of Ottawa; CanadáFil: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos. Mayo Clinic; Estados Unidos. Academy of Athens; GreciaMDPI AG2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/132522Menendez, Javier A.; Mehmi, Inderjit; Papadimitropoulou, Adriana; Steen, Travis Vander; Cuyàs, Elisabet; et al.; Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer; MDPI AG; International Journal of Molecular Sciences; 21; 20; 10-2020; 1-141661-65961422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/21/20/7661info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21207661info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:50Zoai:ri.conicet.gov.ar:11336/132522instacron: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 09:34:50.358CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
title Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
spellingShingle Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
Menendez, Javier A.
ENDOCRINE RESISTANCE
FULVESTRANT
LUMINAL
TAMOXIFEN
title_short Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
title_full Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
title_fullStr Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
title_full_unstemmed Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
title_sort Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer
dc.creator.none.fl_str_mv Menendez, Javier A.
Mehmi, Inderjit
Papadimitropoulou, Adriana
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Vellón, Luciano
Atlas, Ella
Lupu, Ruth
author Menendez, Javier A.
author_facet Menendez, Javier A.
Mehmi, Inderjit
Papadimitropoulou, Adriana
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Vellón, Luciano
Atlas, Ella
Lupu, Ruth
author_role author
author2 Mehmi, Inderjit
Papadimitropoulou, Adriana
Steen, Travis Vander
Cuyàs, Elisabet
Verdura, Sara
Espinoza, Ingrid
Vellón, Luciano
Atlas, Ella
Lupu, Ruth
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ENDOCRINE RESISTANCE
FULVESTRANT
LUMINAL
TAMOXIFEN
topic ENDOCRINE RESISTANCE
FULVESTRANT
LUMINAL
TAMOXIFEN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2-breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.
Fil: Menendez, Javier A.. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; España
Fil: Mehmi, Inderjit. The Angeles Clinic And Research Institute; Estados Unidos
Fil: Papadimitropoulou, Adriana. Academy of Athens; Grecia
Fil: Steen, Travis Vander. Mayo Clinic; Estados Unidos
Fil: Cuyàs, Elisabet. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España. Institut Català d'Oncologia ; España
Fil: Verdura, Sara. Institut Català d'Oncologia ; España. Institut D'investigació Biomèdica de Girona Dr. Josep Trueta; España
Fil: Espinoza, Ingrid. University of Mississippi; 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: Atlas, Ella. University of Ottawa; Canadá
Fil: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos. Mayo Clinic; Estados Unidos. Academy of Athens; Grecia
description HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2-breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.
publishDate 2020
dc.date.none.fl_str_mv 2020-10
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/11336/132522
Menendez, Javier A.; Mehmi, Inderjit; Papadimitropoulou, Adriana; Steen, Travis Vander; Cuyàs, Elisabet; et al.; Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer; MDPI AG; International Journal of Molecular Sciences; 21; 20; 10-2020; 1-14
1661-6596
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/132522
identifier_str_mv Menendez, Javier A.; Mehmi, Inderjit; Papadimitropoulou, Adriana; Steen, Travis Vander; Cuyàs, Elisabet; et al.; Fatty acid synthase is a key enabler for endocrine resistance in heregulin-overexpressing luminal b-like breast cancer; MDPI AG; International Journal of Molecular Sciences; 21; 20; 10-2020; 1-14
1661-6596
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/21/20/7661
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21207661
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 MDPI AG
publisher.none.fl_str_mv MDPI AG
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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