Transglutaminase 2 and NF-κB: an odd couple that shapes breast cancer phenotype

Owing to numerous pro-survival target genes, aberrant activation of the NF-kappa B transcription factor is associated with a drug-resistant phenotype and aggressive breast tumor behavior. Transglutaminase 2 (TG2), a ubiquitously expressed protein cross-linking enzyme, activates NF-kappa B through a non-conventional mechanism that disables the I kappa B alpha inhibitor. Our group has recently documented that the TG2 gene (termed TGM2) is a direct transcriptional target of NF-kappa B. These developments uncover a novel self-reinforcing molecular feedback loop where TG2 activates NF-kappa B and, in turn, NF-kappa B directly upregulates the transcription of TGM2. This manuscript reviews the literature that supports the existence of the TG2/NF-kappa B signaling loop, the nature of the signal transduction that activates this loop, and the phenotypic consequences stemming from the aberrant activation of this novel signaling mechanism in breast cancer.