Inhibition of Specific NF-κB Activity Contributes to the Tumor Suppressor Function of 14-3-3σ in Breast Cancer

14-3-3 sigma is frequently lost in human breast cancers by genetic deletion or promoter methylation. We have now investigated the involvement of 14-3-3 sigma in the termination of NF-kappa B signal in mammary cells and its putative role in cancer relapse and metastasis. Our results show that 14-3-3 sigma regulates nuclear export of p65-NF-kappa B following chronic TNF alpha stimulation. Restoration of 14-3-3 sigma in breast cancer cells reduces migration capacity and metastatic abilities in vivo. By microarray analysis, we have identified a genetic signature that responds to TNF alpha in a 14-3-3 sigma-dependent manner and significantly associates with different breast and other types of cancer. By interrogating public databases, we have found that overexpression of this signature correlates with poor relapse-free survival in breast cancer patients. Finally, screening of 96 human breast tumors showed that NF-kappa B activation strictly correlates with the absence of 14-3-3 sigma 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-kappa B targeting.