1. Inhibition of specific NF-κB activity contributes to the tumor suppressor function of 14-3-3σ in breast cancer.
- Author
-
Inglés-Esteve J, Morales M, Dalmases A, Garcia-Carbonell R, Jené-Sanz A, López-Bigas N, Iglesias M, Ruiz-Herguido C, Rovira A, Rojo F, Albanell J, Gomis RR, Bigas A, and Espinosa L
- Subjects
- 14-3-3 Proteins genetics, Active Transport, Cell Nucleus, Animals, Breast Neoplasms genetics, Breast Neoplasms mortality, Cell Line, Tumor, Cell Movement genetics, Cluster Analysis, Enzyme Activation drug effects, Female, Gene Expression, Gene Expression Profiling, Humans, Mice, NF-kappa B metabolism, Neoplasm Metastasis, Prognosis, Protein Binding drug effects, Survival Analysis, Transcription, Genetic, Tumor Necrosis Factor-alpha pharmacology, Tumor Suppressor Proteins genetics, 14-3-3 Proteins metabolism, Breast Neoplasms metabolism, NF-kappa B antagonists & inhibitors, Tumor Suppressor Proteins metabolism
- Abstract
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.
- Published
- 2012
- Full Text
- View/download PDF