Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer
Editor
Impact JournalsFecha de edición
2013-11-23Cita
Oncotarget 5.1 (2014): 196-210ISSN
1949-2553 (online)Financiado por
Financial support: This work was supported by RD12/0036/0051 (J.A.), RD09/0076/0101, RD09/0076/0036, RD12/0036/0054 (A.B), RD12/0036/0070 (A. Ll), PI12/00680 (J.A.), PI12/01552 (F.R.), PI12/01421 (A.Ll.), 2009 SGR 321 (J.A.), FMM 9757/002 (F.R.), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar Medical Oncology Service. We thank Millenium for generously providing MLN120B.Proyecto
Comunidad de Madrid. S2010/BMD-2344/COLOMICS2Materias
Breast cancer; Chemoresistance; NF-кB; p53; Prognosis; Biología y Biomedicina / BiologíaResumen
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 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 MDAMB-
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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Anexo 2
Google Scholar:Dalmases, Alba
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González, Irene
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Menéndez, Silvia
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Arpí, Oriol
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Corominas, Josep María
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Servitja, Sonia
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Tusquets, Ignasi
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Chamizo, Cristina
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Rincón, Raúl
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Espinosa, Lluis
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Bigas, Anna
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Eroles, Pilar
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Furriol, Jessica
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Lluch, Anna
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Rovira, Ana
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Albanell, Joan
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Rojo, Federico
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