Oncotarget

Research Papers:

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

Alba Dalmases, Irene Gonzalez-Navarrete, Silvia Menendez, Oriol Arpí, Josep Maria Coromines, Sonia Servitja, Ignasi Tusquets, Cristina Chamizo, Raúl Rincón, Lluís Espinosa, Anna Bigas, Pilar Eroles, Jessica Furriol, Anna Lluch, Ana Rovira, Joan Albanell and Federico Rojo _

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Oncotarget. 2014; 5:196-210. https://doi.org/10.18632/oncotarget.1556

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Abstract

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.

Correspondence:

Federico Rojo, email:

Keywords: breast cancer, chemoresistance, NF-кB, p53, prognosis

Received: October 31, 2013 Accepted: November 21, 2013 Published: November 23, 2013

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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