14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα.

14-3-3 tau is frequently overexpressed in breast cancer; however, whether it contributes to breast cancer progression remains undetermined. Here, we identify a critical role for 14-3-3 tau in promoting breast cancer metastasis, in part through binding to and inhibition of RhoGDI alpha, a negative regulator of Rho GTPases and a metastasis suppressor. 14-3-3 tau binds Ser174-phosphorylated RhoGDI alpha and blocks its association with Rho GTPases, thereby promoting epidermal growth factor (EGF)-induced RhoA, Rac1, and Cdc42 activation. When 14-3-3 tau is overexpressed in MCF7 breast cancer cells that express 14-3-3 tau at low levels, it increases motility, reduces adhesion, and promotes metastasis in mammary fat pad xenografts. On the other hand, depletion of 14-3-3 tau in MCF7 cells and in an invasive cell line, MDA-MB231, inhibits Rho GTPase activation and blocks breast cancer migration and invasion. Moreover, 14-3-3 tau overexpression in human breast tumors is associated with the activation of ROCK (a Rho GTPase effector), high metastatic rate, and shorter survival, underscoring a clinically significant role for 14-3-3 tau in breast cancer progression. Our work indicates that 14-3-3 tau is a novel therapeutic target to prevent breast cancer metastasis.