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

Unc5 Netrin Receptor C (UNC5C) is a netrin1 dependence receptor that mediates the induction of apoptosis in the absence of netrin1. The present study found that UNC5C is heterogeneously expressed in breast cancer cell lines. By knocking down UNC5C in SKBR3 and ZR7530 cells and overexpressing UNC5c in MDAMB231 cells, it was demonstrated that UNC5C exerts an inhibitory effect on the growth and metastasis of breast cancer cells. The mechanism involved a UNC5Cknockdowninduced 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 alpha6, which is involved in the growth and metastasis of breast cancer cells. Additionally, UNC5Cknockdown enhanced the phosphorylation of FAK and SRC, which are key kinases in the netrin1/Unc5C and netrin1/integrin alpha6/beta4 signaling pathways. This suggests that netrin1 functions as an integrator for both the netrin1/Unc5C and netrin1/integrin alpha6/beta4 signaling pathways. UNC5Cknockdown potentiated netrin1/integrin alpha6/beta4 signaling. Given that UNC5Cknockdown inhibited integrinliked protein kinase phosphorylation at Thr173, at least in SKBR3 cells, this may be an inhibitory phosphorylation site rather than activating phosphorylation site for relaying integrin signaling.