Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer

Autores
Sevic, Ina; Vitale, Daiana Luján; Morán Maidana, Candela; Rosales, Paolo; Icardi, Antonella; Latina, Catalina; Romano, Lucia; Brandone, Alejandra; Giannoni, Paula; Alaniz, Laura Daniela
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Breast and colorectal cancers remain among the leading causes of cancer-related deaths globally, with therapy failure often driven by tumor complexity and interactions with the tumor microenvironment (TME). Hyaluronic acid (HA), a key extracellular matrix component, plays a vital role in TME remodeling, while altered breast cancer gene 1 and 2 (BRCA1/2) expression, essential for DNA repair, is linked to cancer aggressiveness. This study investigates the link between HA metabolism and BRCA1/2 expression in breast and colorectal cancers. We analyzed HA, CD44, and BRCA1 and 2 expression in patient tissue samples via immunofluorescence. To assess whether HA metabolism affects BRCA1/2 expression, we treated spheroids with hyaluronidase (HYAL) and 4-methylumbelliferone (4-MU) to reduce HA levels. The resulting changes in BRCA1/2 expression were evaluated using qPCR, and tumor profiles were assessed through microscopy and immunofluorescence. We found a coordinated behavior between BRCA1 and BRCA2 in breast cancer and observed BRCA1’s crypt-restricted expression in normal colorectal tissue, which may underlie its well-known tissue specificity. In a triple-negative breast cancer model, we observed that 4-MU reduced spheroid volume and increased BRCA 1/2 levels, suggesting a potential mechanism of 4-MU for tumor shrinkage and BRCA restoration. These findings suggest that 4-MU, a compound already approved for oral use in hepatobiliary indications in Europe and Asia, is a mechanistically plausible HA-targeting candidate for therapeutic repurposing in BRCA-deficient tumors.
Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Morán Maidana, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Rosales, Paolo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Icardi, Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Latina, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Romano, Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Brandone, Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Doctor Abraham Felix Piñeyro.; Argentina
Fil: Giannoni, Paula. Clínica Centro; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Materia
Tumor microenvironment
BRCA1
BRCA2
Hyaluronan metabolism
Breast cancer
Colorectal cancer
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:11336/279004
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast CancerSevic, InaVitale, Daiana LujánMorán Maidana, CandelaRosales, PaoloIcardi, AntonellaLatina, CatalinaRomano, LuciaBrandone, AlejandraGiannoni, PaulaAlaniz, Laura DanielaTumor microenvironmentBRCA1BRCA2Hyaluronan metabolismBreast cancerColorectal cancerhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Breast and colorectal cancers remain among the leading causes of cancer-related deaths globally, with therapy failure often driven by tumor complexity and interactions with the tumor microenvironment (TME). Hyaluronic acid (HA), a key extracellular matrix component, plays a vital role in TME remodeling, while altered breast cancer gene 1 and 2 (BRCA1/2) expression, essential for DNA repair, is linked to cancer aggressiveness. This study investigates the link between HA metabolism and BRCA1/2 expression in breast and colorectal cancers. We analyzed HA, CD44, and BRCA1 and 2 expression in patient tissue samples via immunofluorescence. To assess whether HA metabolism affects BRCA1/2 expression, we treated spheroids with hyaluronidase (HYAL) and 4-methylumbelliferone (4-MU) to reduce HA levels. The resulting changes in BRCA1/2 expression were evaluated using qPCR, and tumor profiles were assessed through microscopy and immunofluorescence. We found a coordinated behavior between BRCA1 and BRCA2 in breast cancer and observed BRCA1’s crypt-restricted expression in normal colorectal tissue, which may underlie its well-known tissue specificity. In a triple-negative breast cancer model, we observed that 4-MU reduced spheroid volume and increased BRCA 1/2 levels, suggesting a potential mechanism of 4-MU for tumor shrinkage and BRCA restoration. These findings suggest that 4-MU, a compound already approved for oral use in hepatobiliary indications in Europe and Asia, is a mechanistically plausible HA-targeting candidate for therapeutic repurposing in BRCA-deficient tumors.Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Morán Maidana, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Rosales, Paolo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Icardi, Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Latina, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Romano, Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Brandone, Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Doctor Abraham Felix Piñeyro.; ArgentinaFil: Giannoni, Paula. Clínica Centro; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaMultidisciplinary Digital Publishing Institute2025-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/279004Sevic, Ina; Vitale, Daiana Luján; Morán Maidana, Candela; Rosales, Paolo; Icardi, Antonella; et al.; Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer; Multidisciplinary Digital Publishing Institute; International Journal of Molecular Sciences; 26; 23; 11-2025; 1-221422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/26/23/11328info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms262311328info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-06T12:13:29Zoai:ri.conicet.gov.ar:11336/279004instacron: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:34982026-02-06 12:13:29.667CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
title Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
spellingShingle Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
Sevic, Ina
Tumor microenvironment
BRCA1
BRCA2
Hyaluronan metabolism
Breast cancer
Colorectal cancer
title_short Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
title_full Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
title_fullStr Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
title_full_unstemmed Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
title_sort Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer
dc.creator.none.fl_str_mv Sevic, Ina
Vitale, Daiana Luján
Morán Maidana, Candela
Rosales, Paolo
Icardi, Antonella
Latina, Catalina
Romano, Lucia
Brandone, Alejandra
Giannoni, Paula
Alaniz, Laura Daniela
author Sevic, Ina
author_facet Sevic, Ina
Vitale, Daiana Luján
Morán Maidana, Candela
Rosales, Paolo
Icardi, Antonella
Latina, Catalina
Romano, Lucia
Brandone, Alejandra
Giannoni, Paula
Alaniz, Laura Daniela
author_role author
author2 Vitale, Daiana Luján
Morán Maidana, Candela
Rosales, Paolo
Icardi, Antonella
Latina, Catalina
Romano, Lucia
Brandone, Alejandra
Giannoni, Paula
Alaniz, Laura Daniela
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Tumor microenvironment
BRCA1
BRCA2
Hyaluronan metabolism
Breast cancer
Colorectal cancer
topic Tumor microenvironment
BRCA1
BRCA2
Hyaluronan metabolism
Breast cancer
Colorectal cancer
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Breast and colorectal cancers remain among the leading causes of cancer-related deaths globally, with therapy failure often driven by tumor complexity and interactions with the tumor microenvironment (TME). Hyaluronic acid (HA), a key extracellular matrix component, plays a vital role in TME remodeling, while altered breast cancer gene 1 and 2 (BRCA1/2) expression, essential for DNA repair, is linked to cancer aggressiveness. This study investigates the link between HA metabolism and BRCA1/2 expression in breast and colorectal cancers. We analyzed HA, CD44, and BRCA1 and 2 expression in patient tissue samples via immunofluorescence. To assess whether HA metabolism affects BRCA1/2 expression, we treated spheroids with hyaluronidase (HYAL) and 4-methylumbelliferone (4-MU) to reduce HA levels. The resulting changes in BRCA1/2 expression were evaluated using qPCR, and tumor profiles were assessed through microscopy and immunofluorescence. We found a coordinated behavior between BRCA1 and BRCA2 in breast cancer and observed BRCA1’s crypt-restricted expression in normal colorectal tissue, which may underlie its well-known tissue specificity. In a triple-negative breast cancer model, we observed that 4-MU reduced spheroid volume and increased BRCA 1/2 levels, suggesting a potential mechanism of 4-MU for tumor shrinkage and BRCA restoration. These findings suggest that 4-MU, a compound already approved for oral use in hepatobiliary indications in Europe and Asia, is a mechanistically plausible HA-targeting candidate for therapeutic repurposing in BRCA-deficient tumors.
Fil: Sevic, Ina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Morán Maidana, Candela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Rosales, Paolo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Icardi, Antonella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Latina, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Romano, Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
Fil: Brandone, Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Doctor Abraham Felix Piñeyro.; Argentina
Fil: Giannoni, Paula. Clínica Centro; Argentina
Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina
description Breast and colorectal cancers remain among the leading causes of cancer-related deaths globally, with therapy failure often driven by tumor complexity and interactions with the tumor microenvironment (TME). Hyaluronic acid (HA), a key extracellular matrix component, plays a vital role in TME remodeling, while altered breast cancer gene 1 and 2 (BRCA1/2) expression, essential for DNA repair, is linked to cancer aggressiveness. This study investigates the link between HA metabolism and BRCA1/2 expression in breast and colorectal cancers. We analyzed HA, CD44, and BRCA1 and 2 expression in patient tissue samples via immunofluorescence. To assess whether HA metabolism affects BRCA1/2 expression, we treated spheroids with hyaluronidase (HYAL) and 4-methylumbelliferone (4-MU) to reduce HA levels. The resulting changes in BRCA1/2 expression were evaluated using qPCR, and tumor profiles were assessed through microscopy and immunofluorescence. We found a coordinated behavior between BRCA1 and BRCA2 in breast cancer and observed BRCA1’s crypt-restricted expression in normal colorectal tissue, which may underlie its well-known tissue specificity. In a triple-negative breast cancer model, we observed that 4-MU reduced spheroid volume and increased BRCA 1/2 levels, suggesting a potential mechanism of 4-MU for tumor shrinkage and BRCA restoration. These findings suggest that 4-MU, a compound already approved for oral use in hepatobiliary indications in Europe and Asia, is a mechanistically plausible HA-targeting candidate for therapeutic repurposing in BRCA-deficient tumors.
publishDate 2025
dc.date.none.fl_str_mv 2025-11
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/11336/279004
Sevic, Ina; Vitale, Daiana Luján; Morán Maidana, Candela; Rosales, Paolo; Icardi, Antonella; et al.; Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer; Multidisciplinary Digital Publishing Institute; International Journal of Molecular Sciences; 26; 23; 11-2025; 1-22
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/279004
identifier_str_mv Sevic, Ina; Vitale, Daiana Luján; Morán Maidana, Candela; Rosales, Paolo; Icardi, Antonella; et al.; Alteration of Hyaluronic Acid Metabolism in Tumor Microenvironment Can Modulate DNA Repair Gene Expression: Therapeutic Potential for Triple-Negative Breast Cancer; Multidisciplinary Digital Publishing Institute; International Journal of Molecular Sciences; 26; 23; 11-2025; 1-22
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/1422-0067/26/23/11328
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms262311328
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
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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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