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

Dalmases Massegú, Alba, 1982-González González, IreneMenendez Romero, SilviaArpí Llucià, OriolCorominas Torres, Josep MariaServitja Tormo, SoniaTusquets Trias de Bes, IgnacioChamizo, CristinaRincón, RaúlEspinosa Blay, LluísBigas Salvans, AnnaEroles, PilarFurriol, JessicaLluch, AnaRovira Guerín, AnaAlbanell Mestres, JoanRojo, Federico2019-07-102019-07-102014Dalmases 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.15561949-2553http://hdl.handle.net/10230/41974NF-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.application/pdfeng© 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 creditedMama -- CàncerMedicaments antineoplàsticsDuxorubicinaProteïnes supressores de tumorsDeficiency in p53 is required for doxorubicin induced transcriptional activation of NF-κB target genes in human breast cancerinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.18632/oncotarget.1556info:eu-repo/semantics/openAccess