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

Alba Dalmases, Irene González, Silvia Menendez, Oriol Arpí, Josep Maria Corominas, Sonia Servitja, Ignasi Tusquets, Cristina Chamizo, Raúl Rincón, Lluis Espinosa, Anna Bigas, Pilar Eroles, Jessica Furriol, Anna Lluch, Ana Rovira, Joan Albanell, Federico Rojo

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

NF-κB has been linked to doxorubicin resistance in breast cancer patients. NF-κB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-κB-dependent genes and the biological consequences are unclear. We studied NF-κB-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-κB -dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKß-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-κB 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 NF-κB 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-κB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDAMB-231 cells impaired NF-κB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-κB /p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-κB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.
Original languageEnglish
Pages (from-to)196-210
JournalOncotarget
Volume5
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Breast cancer
  • Chemoresistance
  • NF-κB
  • p53
  • Prognosis

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