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Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer

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dc.contributor.author Pascual-Reguant, Laura
dc.contributor.author Datta, Debayan
dc.contributor.author Cianferoni, Damiano
dc.contributor.author Kourtis, Savvas
dc.contributor.author Gañez-Zapater, Antoni
dc.contributor.author Cannatá, Chiara
dc.contributor.author Espinar, Lorena
dc.contributor.author García López, Laura
dc.contributor.author Musa-Afaneh, Sara
dc.contributor.author Guirola, Maria
dc.contributor.author Gkanogiannis, Anestis
dc.contributor.author Miró Canturri, Andrea
dc.contributor.author Arribas, Joaquín
dc.contributor.author Serrano Pubull, Luis, 1982-
dc.contributor.author Sdelci, Sara
dc.date.accessioned 2024-02-08T07:10:05Z
dc.date.available 2024-02-08T07:10:05Z
dc.date.issued 2023
dc.identifier.citation Pascual-Reguant L, Serra-Camprubí Q, Datta D, Cianferoni D, Kourtis S, Gañez-Zapater A et al. Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer. EMBO Mol Med. 2023 Dec 7;15(12):e18459. DOI: 10.15252/emmm.202318459
dc.identifier.issn 1757-4676
dc.identifier.uri http://hdl.handle.net/10230/58994
dc.description.abstract Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC.
dc.description.sponsorship We thank Pharmaxis for the supply of PXS LOXL2 inhibitors. SS is supported by the Plan Estatal de I + D + I (COMBAT PID2019‐110598GA‐I00), and the ERC Starting Grant (ERC‐StG‐852343‐EPICAMENTE). LP‐R is supported by the Juan de la Cierva‐Formación fellowship (FJC2019‐040598‐I) and Fundación Franscico Cobos fellowship. TVT is supported by Plan Estatal de I + D + I (PID2019‐108008RJ‐I00), AECC (INVES20036TIAN), and a Ramón y Cajal investigator contract (RYC2020‐029098‐I). DC is supported by the la Caixa Foundation PhD fellowship (ID 100010434; fellowship code LCF/BQ/DI19/11730061).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher EMBO Press
dc.relation.ispartof EMBO Mol Med. 2023 Dec 7;15(12):e18459
dc.rights © 2023 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.15252/emmm.202318459
dc.subject.keyword Cell cycle
dc.subject.keyword Combinatorial therapy
dc.subject.keyword Gene expression
dc.subject.keyword Triple-negative breast cancer
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/852343
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019‐110598GA‐I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/FJC2019‐040598‐I
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019‐108008RJ‐I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RYC2020‐029098‐I
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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