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, Ignasi |
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 |
2014 |
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.citation |
1949-2553 |
dc.identifier.citation |
http://dx.doi.org/10.18632/oncotarget.1556 |
dc.identifier.uri |
http://hdl.handle.net/10230/41974 |
dc.format |
application/pdf |
dc.language.iso |
eng |
dc.publisher |
Impact Journals |
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 |
https://creativecommons.org/licenses/by/3.0/ |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Mama -- Càncer |
dc.subject |
Medicaments antineoplàstics |
dc.subject |
Duxorubicina |
dc.subject |
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 |
info:eu-repo/semantics/publishedVersion |
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.abstract |
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 |