Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer

Autores
Toro, Carla; Real Varela, Sebastián Martín; Laurito, Sergio Roberto; Branham, Maria Teresita
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer.
Fil: Toro, Carla. Universidad Nacional de Cuyo; Argentina
Fil: Real Varela, Sebastián Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Laurito, Sergio Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Materia
ID4
TRIPLE NEGATIVE
BREAST CANCER
DRIVER
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/287162
Acceder
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast CancerToro, CarlaReal Varela, Sebastián MartínLaurito, Sergio RobertoBranham, Maria TeresitaID4TRIPLE NEGATIVEBREAST CANCERDRIVERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer.Fil: Toro, Carla. Universidad Nacional de Cuyo; ArgentinaFil: Real Varela, Sebastián Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Laurito, Sergio Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaCold Spring Harbor Laboratory Press2025-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/287162Toro, Carla; Real Varela, Sebastián Martín; Laurito, Sergio Roberto; Branham, Maria Teresita; Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer; Cold Spring Harbor Laboratory Press; BioRxiv; 11; 69; 2-2025; 1-192692-8205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41523-025-00787-yinfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41523-025-00787-yinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:53:34Zoai:ri.conicet.gov.ar:11336/287162instacron: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:34982026-08-25 14:53:35.6CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
title Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
spellingShingle Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
Toro, Carla
ID4
TRIPLE NEGATIVE
BREAST CANCER
DRIVER
title_short Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
title_full Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
title_fullStr Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
title_full_unstemmed Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
title_sort Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer
dc.creator.none.fl_str_mv Toro, Carla
Real Varela, Sebastián Martín
Laurito, Sergio Roberto
Branham, Maria Teresita
author Toro, Carla
author_facet Toro, Carla
Real Varela, Sebastián Martín
Laurito, Sergio Roberto
Branham, Maria Teresita
author_role author
author2 Real Varela, Sebastián Martín
Laurito, Sergio Roberto
Branham, Maria Teresita
author2_role author
author
author
dc.subject.none.fl_str_mv ID4
TRIPLE NEGATIVE
BREAST CANCER
DRIVER
topic ID4
TRIPLE NEGATIVE
BREAST CANCER
DRIVER
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer.
Fil: Toro, Carla. Universidad Nacional de Cuyo; Argentina
Fil: Real Varela, Sebastián Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Laurito, Sergio Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Fil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
description Basal-like breast cancer (BLBC) is an aggressive subtype with poor prognosis and limited treatment options. The Inhibitor of Differentiation 4 (ID4) protein is frequently overexpressed in BLBC, yet its role in tumor progression remains unclear. Here, we used CRISPR–Cas9-mediated ID4 knockout, pharmacologic inhibition, in vivo xenografts, and transcriptomic analysis to investigate ID4 function. ID4 loss in MDA-MB-231 cells reduced proliferation, colony formation, Ki67 expression, and tumor growth in vivo. TCGA analysis showed improved relapse-free survival in patients with low ID4 expression. Gene set enrichment revealed a luminal-like transcriptional profile in ID4-low tumors, including increased estrogen response and inflammatory signaling. Transcription factor activity analysis indicated MYC, JUN, and STAT activation, suggesting a shift toward differentiation. The ID4 degrader AGX51 also suppressed TNBC cell proliferation. Together, these findings identify ID4 as a driver of BLBC aggressiveness and support its inhibition as a promising therapeutic strategy for improving outcomes in triple-negative breast cancer.
publishDate 2025
dc.date.none.fl_str_mv 2025-02
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/11336/287162
Toro, Carla; Real Varela, Sebastián Martín; Laurito, Sergio Roberto; Branham, Maria Teresita; Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer; Cold Spring Harbor Laboratory Press; BioRxiv; 11; 69; 2-2025; 1-19
2692-8205
CONICET Digital
CONICET
url http://hdl.handle.net/11336/287162
identifier_str_mv Toro, Carla; Real Varela, Sebastián Martín; Laurito, Sergio Roberto; Branham, Maria Teresita; Exploring ID4 as a Driver of Aggression and a Therapeutic Target in Triple-Negative Breast Cancer; Cold Spring Harbor Laboratory Press; BioRxiv; 11; 69; 2-2025; 1-19
2692-8205
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.nature.com/articles/s41523-025-00787-y
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41523-025-00787-y
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
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 13.265058

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