ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity

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dc.contributor.authorZamora Álvarez, Irene
dc.contributor.authorGutiérrez Núñez, Mirian
dc.contributor.authorPascual, Alex
dc.contributor.authorPajares Villandiego, María Josefa
dc.contributor.authorBarajas Vélez, Miguel Ángel
dc.contributor.authorPerez, Lillian M.
dc.contributor.authorYou, Sungyong
dc.contributor.authorKnudsen, Beatrice S.
dc.contributor.authorFreeman, Michael R.
dc.contributor.authorEncío Martínez, Ignacio
dc.contributor.authorRotinen Díaz, Mirja Sofia
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.departmentInstitute for Multidisciplinary Research in Applied Biology - IMABen
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernua
dc.date.accessioned2024-11-07T11:16:34Z
dc.date.available2024-11-07T11:16:34Z
dc.date.issued2024-05-31
dc.date.updated2024-11-07T10:58:24Z
dc.description.abstractPurpose: tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. Methods: we analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. Results: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. Conclusions: the transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.en
dc.description.sponsorshipThis research was funded by the Spanish Ministry of Science, Innovation and Universities, grant number: PID2019-109577RA-I00/AEI/10.13039/501100011033 (M.R.); The Spanish Ministry of Science, Innovation and Universities (Ramón y Cajal Program) grant number: RYC-2018-023874-I (M.R.); 2021/22 Predoctoral Fellowship UPNA-RYC program (M.G.); The Spanish Ministry of Science, Innovation and Universities, grant number: FPU22/03658 (I.Z.); Department of Health, Government of Navarre, grant number: 026/2022 (M.R.).
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/msworden
dc.identifier.citationZamora, I., Gutiérrez, M., Pascual, A., Pajares, M. J., Barajas, M., Perez, L. M., You, S., Knudsen, B. S., Freeman, M. R., Encío, I. J., Rotinen, M. (2024). ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity. Cellular Oncology. https://doi.org/10.1007/s13402-024-00957-3.
dc.identifier.doi10.1007/s13402-024-00957-3
dc.identifier.issn2211-3428
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52465
dc.language.isoeng
dc.publisherSringer
dc.relation.ispartofCellular Oncology (2024)
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-109577RA-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICIU//RYC-2018-023874-I/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MICIU//FPU22%2F03658/
dc.relation.projectIDinfo:eu-repo/grantAgreement/Gobierno de Navarra//026%2F2022/
dc.relation.publisherversionhttps://doi.org/10.1007/s13402-024-00957-3
dc.rights© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBreast canceren
dc.subjectCell plasticityen
dc.subjectEstrogen receptoren
dc.subjectHeterogeneityen
dc.subjectONECUT2en
dc.subjectTranscription factoren
dc.titleONECUT2 is a druggable driver of luminal to basal breast cancer plasticityen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication1863d4fc-a2fd-4dfe-8700-d366cf8c6273
relation.isAuthorOfPublication601df8fd-4b6f-47c4-be5d-4b81d2c1cf64
relation.isAuthorOfPublication2e998efa-ca5a-491e-9e7f-a8fbbd0094ce
relation.isAuthorOfPublication599ca381-1fd2-4a23-93ab-4373837eb6e0
relation.isAuthorOfPublicationecbb6fbe-3bda-4cad-945f-f263c1af5981
relation.isAuthorOfPublication.latestForDiscovery1863d4fc-a2fd-4dfe-8700-d366cf8c6273

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