Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer

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• dc.contributor.author Dalmases Massegú, Alba, 1982-
• dc.contributor.author González González, Irene
• dc.contributor.author Menendez Romero, Silvia
• dc.contributor.author Arpí Llucià, Oriol
• dc.contributor.author Corominas Torres, Josep Maria
• dc.contributor.author Servitja Tormo, Sonia
• dc.contributor.author Tusquets Trias de Bes, Ignacio
• dc.contributor.author Chamizo, Cristina
• dc.contributor.author Rincón, Raúl
• dc.contributor.author Espinosa Blay, Lluís
• dc.contributor.author Bigas Salvans, Anna
• dc.contributor.author Eroles, Pilar
• dc.contributor.author Furriol, Jessica
• dc.contributor.author Lluch, Ana
• dc.contributor.author Rovira Guerín, Ana
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Rojo, Federico
• dc.date.accessioned 2019-07-10T07:23:51Z
• dc.date.available 2019-07-10T07:23:51Z
• dc.date.issued 2014
• dc.description.abstract NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
• dc.description.sponsorship This work was supported by RD12/0036/0051 (J.A.), RD09/0076/0101, RD09/0076/0036, RD12/0036/0054 (A.B), RD12/0036/0070 (A. Ll), PI12/00680 (J.A.), PI12/01552 (F.R.), PI12/01421 (A.Ll.), 2009 SGR 321 (J.A.), FMM 9757/002 (F.R.), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar Medical Oncology Service. We thank Millenium for generously providing MLN120B
• dc.format.mimetype application/pdf
• dc.identifier.citation Dalmases A, González I, Menendez S, Arpí O, Corominas JM, Servitja S et al. Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer. Oncotarget. 2014 Jan;5(1):196-210. DOI: 10.18632/oncotarget.1556
• dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.1556
• dc.identifier.issn 1949-2553
• dc.identifier.uri http://hdl.handle.net/10230/41974
• dc.language.iso eng
• dc.publisher Impact Journals
• dc.relation.ispartof Oncotarget. 2014 Jan;5(1):196-210
• dc.rights © 2014 Dalmases et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/3.0/
• dc.subject.other Mama -- Càncer
• dc.subject.other Medicaments antineoplàstics
• dc.subject.other Duxorubicina
• dc.subject.other Proteïnes supressores de tumors
• dc.title Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion