Persistent activation of STAT3 by PIM2-driven positive feedback loop for epithelial-mesenchymal transition in breast cancer

Abstract

Metastasis of breast cancer is promoted by epithelial-mesenchymal transition (EMT). Emerging evidence suggests that STAT3 is a critical signaling node in EMT and is constitutively activated in many carcinomas, including breast cancer. However, its signaling mechanisms underlying persistent activation of STAT3 associated with EMT remain obscure. Here, we report that PIM2 promotes activation of STAT3 through induction of cytokines. Activation of STAT3 caused an increase in PIM2 expression, implicating a positive feedback loop between PIM2 and STAT3. In agreement, targeting of either PIM2, STAT3 or PIM2-dependent cytokines suppressed EMT-associated migratory and invasive properties through inhibition of ZEB1. Taken together, our findings identify the signaling mechanisms underlying the persistent activation of STAT3 and the oncogenic role of PIM2 in EMT in breast cancer. PIM2 promotes epithelial-mesenchymal transition through activation of STAT3. PIM2 activates STAT3 through induction of IL-8 in breast cancer cells. STAT3 is constitutively activated by PIM2-driven positive feedback loop.