Activation of NF-kappaB is reported in breast cancers. NF-kappaB inhibition in breast cancer cell lines results in an increase in apoptosis. However, the reason for continuous activation of this transcription factor in breast cancer is currently unclear. Interestingly, elevated transglutaminase 2 (TGase 2) expression is additionally observed in breast cancer. Recent studies showed that doxorubicin-resistant cells contain a higher level of TGase 2, compared to doxorubicin-sensitive cells. Moreover, increasing the level of TGase 2 in breast cancer cells by transient transfection leads to decreased expression of the inhibitory subunit ?of NF-kappaB (I-kappaBA), and up regulation of NF-kappaB activity. Our data show that TGase 2 expression is inversely correlated with the level of I-kappaBa in breast tumors, implying that the enzyme is responsible for the constitutive activation of NF-kappaB in breast tumors.