Inhibition of specific NF-κB activity contributes to the tumor suppressor function of 14-3-3σ in breast cancer.
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.
Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
Julia
J
Inglés-Esteve
Mònica
M
Morales
Alba
A
Dalmases
Ricard
R
Garcia-Carbonell
Alba
A
Jené-Sanz
Núria
N
López-Bigas
Mar
M
Iglesias
Cristina
C
Ruiz-Herguido
Ana
A
Rovira
Federico
F
Rojo
Joan
J
Albanell
Roger R
RR
Gomis
Anna
A
Bigas
Lluís
L
Espinosa
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016000:Cluster Analysis; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009362:Neoplasm Metastasis; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D016019:Survival Analysis; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins