Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer
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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202318459 |
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| author | Laura Pascual‐Reguant Queralt Serra‐Camprubí Debayan Datta Damiano Cianferoni Savvas Kourtis Antoni Gañez‐Zapater Chiara Cannatá Lorena Espinar Jessica Querol Laura García‐López Sara Musa‐Afaneh Maria Guirola Anestis Gkanogiannis Andrea Miró Canturri Marta Guzman Olga Rodríguez Andrea Herencia‐Ropero Joaquin Arribas Violeta Serra Luis Serrano Tian V Tian Sandra Peiró Sara Sdelci |
| author_facet | Laura Pascual‐Reguant Queralt Serra‐Camprubí Debayan Datta Damiano Cianferoni Savvas Kourtis Antoni Gañez‐Zapater Chiara Cannatá Lorena Espinar Jessica Querol Laura García‐López Sara Musa‐Afaneh Maria Guirola Anestis Gkanogiannis Andrea Miró Canturri Marta Guzman Olga Rodríguez Andrea Herencia‐Ropero Joaquin Arribas Violeta Serra Luis Serrano Tian V Tian Sandra Peiró Sara Sdelci |
| author_sort | Laura Pascual‐Reguant |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-a9ac7e4ea8d342f3a90f379ec5eb682e |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a9ac7e4ea8d342f3a90f379ec5eb682e2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-11-01151212310.15252/emmm.202318459Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancerLaura Pascual‐Reguant0Queralt Serra‐Camprubí1Debayan Datta2Damiano Cianferoni3Savvas Kourtis4Antoni Gañez‐Zapater5Chiara Cannatá6Lorena Espinar7Jessica Querol8Laura García‐López9Sara Musa‐Afaneh10Maria Guirola11Anestis Gkanogiannis12Andrea Miró Canturri13Marta Guzman14Olga Rodríguez15Andrea Herencia‐Ropero16Joaquin Arribas17Violeta Serra18Luis Serrano19Tian V Tian20Sandra Peiró21Sara Sdelci22Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyVall d'Hebron Institute of Oncology (VHIO)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyVall d'Hebron Institute of Oncology (VHIO)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyVall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyVall d'Hebron Institute of Oncology (VHIO)Vall d'Hebron Institute of Oncology (VHIO)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and TechnologyAbstract 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.https://doi.org/10.15252/emmm.202318459cell cyclecombinatorial therapygene expressiontriple‐negative breast cancer |
| spellingShingle | Laura Pascual‐Reguant Queralt Serra‐Camprubí Debayan Datta Damiano Cianferoni Savvas Kourtis Antoni Gañez‐Zapater Chiara Cannatá Lorena Espinar Jessica Querol Laura García‐López Sara Musa‐Afaneh Maria Guirola Anestis Gkanogiannis Andrea Miró Canturri Marta Guzman Olga Rodríguez Andrea Herencia‐Ropero Joaquin Arribas Violeta Serra Luis Serrano Tian V Tian Sandra Peiró Sara Sdelci Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer EMBO Molecular Medicine cell cycle combinatorial therapy gene expression triple‐negative breast cancer |
| title | Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer |
| title_full | Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer |
| title_fullStr | Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer |
| title_full_unstemmed | Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer |
| title_short | Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple‐negative breast cancer |
| title_sort | interactions between brd4s loxl2 and med1 drive cell cycle transcription in triple negative breast cancer |
| topic | cell cycle combinatorial therapy gene expression triple‐negative breast cancer |
| url | https://doi.org/10.15252/emmm.202318459 |
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