A set of accessible enhancers enables the initial response of breast cancer cells to physiological progestin concentrations

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• dc.contributor.author Zaurín Quer, Roser
• dc.contributor.author Ferrari, Roberto
• dc.contributor.author Nacht, A. Silvina
• dc.contributor.author Carbonell-Caballero, Jose
• dc.contributor.author Le Dily, François
• dc.contributor.author Font Mateu, Jofre, 1977-
• dc.contributor.author De Llobet, Lara Isabel
• dc.contributor.author Vidal Ocabo, Enrique
• dc.contributor.author Lioutas, Antonio, 1980-
• dc.contributor.author Beato, Miguel
• dc.contributor.author Vincent, Guillermo P.
• dc.date.accessioned 2022-04-01T09:19:33Z
• dc.date.available 2022-04-01T09:19:33Z
• dc.date.issued 2021
• dc.description.abstract Here, we report that in T47D breast cancer cells 50 pM progestin is sufficient to activate cell cycle entry and the progesterone gene expression program. At this concentration, equivalent to the progesterone blood levels found around the menopause, progesterone receptor (PR) binds only to 2800 genomic sites, which are accessible to ATAC cleavage prior to hormone exposure. These highly accessible sites (HAs) are surrounded by well-organized nucleosomes and exhibit breast enhancer features, including estrogen receptor alpha (ERα), higher FOXA1 and BRD4 (bromodomain containing 4) occupancy. Although HAs are enriched in RAD21 and CTCF, PR binding is the driving force for the most robust interactions with hormone-regulated genes. HAs show higher frequency of 3D contacts among themselves than with other PR binding sites, indicating colocalization in similar compartments. Gene regulation via HAs is independent of classical coregulators and ATP-activated remodelers, relying mainly on MAP kinase activation that enables PR nuclear engagement. HAs are also preferentially occupied by PR and ERα in breast cancer xenografts derived from MCF-7 cells as well as from patients, indicating their potential usefulness as targets for therapeutic intervention.
• dc.description.sponsorship Funding: Ministerio de Ciencia e Innovación [PID2019-105173RB-I00 and PID2019-110384GB-C21]; Spanish Ministry of Economy and Competitiveness [SAF2016-75006-P and G62426937]; Consejo Superior de Investigaciones Científicas [201820I131]; Centro de Excelencia Severo Ochoa [SEV-2012-2018]; European Research Council [609989]. Funding for open access charge: Ministerio de Ciencia e Innovación
• dc.format.mimetype application/pdf
• dc.identifier.citation Zaurin R, Ferrari R, Nacht AS, Carbonell J, Le Dily F, Font-Mateu J et al. A set of accessible enhancers enables the initial response of breast cancer cells to physiological progestin concentrations. Nucleic Acids Res. 2021 Dec 16;49(22):12716-31. DOI: 10.1093/nar/gkab1125
• dc.identifier.doi http://dx.doi.org/10.1093/nar/gkab1125
• dc.identifier.issn 0305-1048
• dc.identifier.uri http://hdl.handle.net/10230/52813
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75006-P
• dc.rights © Roser Zaurin et al. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-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-nc/4.0/
• dc.subject.other Genètica
• dc.subject.other Mama -- Càncer
• dc.title A set of accessible enhancers enables the initial response of breast cancer cells to physiological progestin concentrations
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion