Figure 3

Tissue transglutaminase (TG2)-regulated inflammatory signaling promotes drug resistance and the metastatic phenotype. Owing to its binding and rapid degradation of the inhibitory protein IκBα, TG2 results in constitutive activation of the pro-inflammatory transcription factor NF-κB. Activated NF-κB (specifically the p65/RelA subunit), in complex with TG2, translocates to the nucleus, where it binds to HIF-1α promoter and results in its transcriptional regulation and protein expression even under normal oxygen levels. Increased expression of HIF-1α, in turn, induces the expression of transcription repressors such as Snail, Zeb, and Twist. Collectively, these TG2/NF-κB/HIF-1α-induced alterations result in acquisition of EMT and stem cell traits. Intracellular TG2 is also known to induce the synthesis and deposition of the ECM component proteins, whereas extracellular TG2 stabilizes the ECM by introducing proteolytic-resistant isopeptide bonds between its component proteins. TG2-induced changes in the ECM can alter cell attachment and cell motility functions. Similarly, TG2-catalyzed crosslinking of the ECM could further contribute to the aggressive phenotype of cancer cells by increasing shear stresses. Membrane-bound TG2, on the other hand, can interact with integrin and growth factor receptors (for example, PDGFR) to induce clustering and downstream signaling. Moreover, membrane-bound and integrin-associated TG2 can interact with fibronectin and further amplify integrin-mediated signaling. In a nutshell, aberrant expression of TG2 initiates reprogramming of the transcription machinery, which in turn initiates a whole new series of inside-out and outside-in signaling pathways to confer an aggressive phenotype to breast cancer cells. BMP7, bone morphogenetic protein 7; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; ERK1/2, extracellular signal-regulated kinase 1/2; FAK, focal adhesion kinase; HIF-1, hypoxia-induced factor-1; IκBα, inhibitory κBα; MMP, matrix metalloproteinase; NF-κB, nuclear transcription factor-kappa B; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; SPARC, secreted protein acidic and rich in cysteine; VEGF, vascular endothelial growth factor.