UNC5C-knockdown enhances the growth and metastasis of breast cancer cells by potentiating the integrin α6/β4 signaling pathway

Unc-5 Netrin Receptor C (UNC5C) is a netrin-1 dependence receptor that mediates the induction of apoptosis in the absence of netrin-1. The present study found that UNC5C is heterogeneously expressed in breast cancer cell lines. By knocking down UNC5C in SK-BR-3 and ZR-75-30 cells and overexpressing UNC5c in MDA-MB-231 cells, it was demonstrated that UNC5C exerts an inhibitory effect on the growth and metastasis of breast cancer cells. The mechanism involved a UNC5C-knockdown-induced enhancement of matrix metalloproteinase (MMP)3, MMP7, MMP9 and MMP10 expression via activation of the PI3K/AKT, ERK and p38 MAPK signaling pathways. Notably, UNC5C directly interacted with integrin α6, which is involved in the growth and metastasis of breast cancer cells. Additionally, UNC5C-knockdown enhanced the phosphorylation of FAK and SRC, which are key kinases in the netrin-1/Unc5C and netrin-1/integrin α6/β4 signaling pathways. This suggests that netrin-1 functions as an integrator for both the netrin-1/Unc5C and netrin-1/integrin α6/β4 signaling pathways. UNC5C-knockdown potentiated netrin-1/integrin α6/β4 signaling. Given that UNC5C-knockdown inhibited integrin-liked protein kinase phosphorylation at Thr-173, at least in SK-BR-3 cells, this may be an inhibitory phosphorylation site rather than activating phosphorylation site for relaying integrin signaling.