TGF-β1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-β1 alone. So far, the mechanisms underlying the induction of TGF-β1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-β1. Intriguingly, TGF-β1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-β1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TβRs. Except for JNK, all of these pathways were required for the effects of TGF-β1 and TNF-α. 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 TβRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-β1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TβRII expression. These findings suggest that the up-regulation of TβRs contributes to the sustained activation of TAK1 induced by TGF-β1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

中文翻译：

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TGF-β1和TNF-α通过增强TAK1激活来协同诱导乳腺癌细胞上皮向间质转化。

TGF-β1是上皮向间质转化（EMT）的主要诱导剂。然而，许多乳腺癌细胞对仅由TGF-β1诱导的EMT不敏感。到目前为止，尚不清楚诱导TGF-β1不敏感的乳腺癌细胞的潜在机制。在这里，我们报道TNF-α可以诱导对TGF-β1不敏感的乳腺癌细胞的EMT和侵袭性。有趣的是，TGF-β1可以与TNF-α协同促进乳腺癌细胞的EMT和侵袭性。与TGF-β1和TNF-α的长时间共刺激可以通过增强TAK1的激活来增强Smad2 / 3，p38 MAPK，ERK，JNK和NF-κB途径的持续激活，而TAK1的激活是由逐渐上调引起的Tβ受体 除JNK外，所有这些途径都是TGF-β1和TNF-α作用所必需的。重要的，p38 MAPK和ERK途径的激活通过上调TβRs的表达，从而促进多种信号途径的激活，从而对TAK1激活产生积极的反馈作用。而且，SLUG被上调并且是TGF-β1/TNF-α诱导的EMT和侵袭性所必需的。此外，SLUG还可以通过促进TβRII表达来增强信号通路的激活。这些发现表明，TβRs的上调有助于TGF-β1/TNF-α诱导的TAK1的持续活化以及随后多种信号通路的活化，从而导致乳腺癌细胞的EMT和侵袭性。SLUG上调，是TGF-β1/TNF-α诱导的EMT和侵袭性所必需的。此外，SLUG还可以通过促进TβRII表达来增强信号通路的激活。这些发现表明，TβRs的上调有助于TGF-β1/TNF-α诱导的TAK1的持续活化以及随后多种信号通路的活化，从而导致EMT和乳腺癌细胞的侵袭性。SLUG上调，是TGF-β1/TNF-α诱导的EMT和侵袭性所必需的。此外，SLUG还可以通过促进TβRII表达来增强信号通路的激活。这些发现表明，TβRs的上调有助于TGF-β1/TNF-α诱导的TAK1的持续活化以及随后多种信号通路的活化，从而导致乳腺癌细胞的EMT和侵袭性。