TGF-β1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation

TGF-beta 1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-beta 1 alone. So far, the mechanisms underlying the induction of TGF-beta 1-insensitive breast cancer cells remains unclear. Here we report that TNF-alpha can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-beta 1. Intriguingly, TGF-beta 1 could cooperate with TNF-alpha to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-beta 1 and TNF-alpha could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-kappa B pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated T beta Rs. Except for JNK, all of these pathways were required for the effects of TGF-beta 1 and TNF-alpha. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of T beta Rs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-beta 1/TNF-alpha-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting T beta RII expression. These findings suggest that the up-regulation of T beta Rs contributes to the sustained activation of TAK1 induced by TGF-beta 1/TNF-alpha and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.