Title:
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Inhibition of specific NF-KB activity contributes to the tumor suppressor function of 14-3-3omega in breast cancer
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Author:
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Inglés Esteve, Julia; Morales, Mònica; Dalmases Massegú, Alba, 1982-; Garcia Carbonell, Ricard; Jené i Sanz, Alba, 1984-; López Bigas, Núria; Iglesias Coma, Mar; Ruiz Herguido, Cristina; Rovira Guerín, Ana; Rojo, Federico; Albanell Mestres, Joan; Gomis, Roger R.; Bigas Salvans, Anna; Espinosa Blay, Lluís
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Abstract:
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14-3-3σ is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3σ in the termination of NF-κB signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3σ regulates nuclear export of p65-NF-κB following chronic TNFα stimulation. Restoration of 14-3-3σ in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that over-expression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-κB activation strictly correlates with the absence of 14-3-3σ and it is significantly associated with worse prognosis in the multivariate analysis. Our findings identify a genetic signature that is important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting. |
Abstract:
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This work was funded by ISCIII/FEDER-Subdirección General de Evaluación y Fomento de la Investigación (PI07/0778, PI10/01128, PS09/1296 and PS09/01285), AGAUR (2009SGR23 and 2009SGR321) and Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), iniciativa Ingenio 2010, Programa Consolider and Instituto de Salud Carlos III (ISCIII)/FEDER (RD06/0020/0098 and RD06/0020/0109). Financial support was provided to RRG by BBVA foundation and Asociación Española Contra el Cáncer. NLB acknowledges funding from the Spanish Ministry of Science and Technology (SAF2009-06954). AJ-S was funded by Science and Education Spanish Ministry (MEC) FPI predoctoral fellowship (BES-2008-001850). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript |
Subject(s):
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-Proteïnes de la sang -Mama -- Càncer -- Aspectes genètics -Antioncogens |
Rights:
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© 2012 Inglés-Esteve et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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Document type:
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Article Article - Published version |
Published by:
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Public Library of Science (PLoS)
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