Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer
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Alba Dalmases1,2, Irene González1,2, Silvia Menendez1,2, Oriol Arpí1,2, Josep Maria Corominas3, Sonia Servitja1,2, Ignasi Tusquets1,2,4, Cristina Chamizo5 , Raúl Rincón5, Lluis Espinosa1, Anna Bigas1, Pilar Eroles6, Jessica Furriol6, Anna Lluch7,8, Ana Rovira1,2, Joan Albanell1,2,9, Federico Rojo1,5
1 Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain;
2 Medical Oncology Department, Hospital del Mar, Barcelona, Spain;
3 Pathology Department, Hospital del Mar, Barcelona, Spain;
4 Autonomous University of Barcelona, Spain;
5 Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain;
6 Institute of Health Research INCLIVA, Valencia, Spain;
7 Oncology and Hematology Department, Hospital Clinico Universitario, Valencia, Spain;
8 Valencia Central University, Spain;
9 Universitat Pompeu Fabra, Barcelona, Spain.
Federico Rojo, email:
Keywords: breast cancer, chemoresistance, NF-кB, p53, prognosis
Received: October 31, 2013 Accepted: November 21, 2013 Published: November 23, 2013
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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