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

Authors
  • Dalmases, Alba
  • González, Irene
  • Menendez, Silvia
  • Arpí, Oriol
  • Corominas, Josep Maria
  • Servitja, Sonia
  • Tusquets, Ignasi
  • Chamizo, Cristina
  • Rincón, Raúl
  • Espinosa, Lluis
  • Bigas, Anna
  • Eroles, Pilar
  • Furriol, Jessica
  • Lluch, Anna
  • Rovira, Ana
  • Albanell, Joan
  • Rojo, Federico
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Jan 15, 2014
Volume
5
Issue
1
Pages
196–210
Identifiers
PMID: 24344116
Source
Medline
License
Unknown

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.

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