Akt/PKB-mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-talk Between PI3K/Akt and TGFβ Signaling Axes
Menée in vivo et sur 1 532 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer invasif du sein, cette étude identifie un mécanisme par lequel la voie de signalisation PI3K/Akt régule l'activation du facteur de transcription Twist1 et favorise le processus métastatique
Metastatic breast tumor cells display an epithelial-mesenchymal transition (EMT) that increases cell motility, invasion and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here we show that Twist1 is ubiquitously phosphorylated in 90% of 1532 invasive human breast tumors. Akt-mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGFβ2, leading to enhanced TGFβ receptor signaling, that in turn maintains hyperactive PI3K/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGFβ2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 in mediating cross-talk between the PI3K/Akt and TGFβ/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event linking PI3K/Akt hyperactivation in tumor cells to direct regulation of Twist1 activation and tumor metastasis.