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, 1990-
  • 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.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.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.doi http://dx.doi.org/10.15252/emmm.202318459
  • dc.identifier.issn 1757-4676
  • dc.identifier.uri http://hdl.handle.net/10230/58994
  • dc.language.iso eng
  • dc.publisher EMBO Press
  • dc.relation.ispartof EMBO Mol Med. 2023 Dec 7;15(12):e18459
  • 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 © 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.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cell cycle
  • dc.subject.keyword Combinatorial therapy
  • dc.subject.keyword Gene expression
  • dc.subject.keyword Triple-negative breast cancer
  • 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.type.version info:eu-repo/semantics/publishedVersion

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