title: 14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα.
abstract: 14-3-3τ is frequently overexpressed in breast cancer; however, whether it contributes to breast cancer progression remains undetermined. Here, we identify a critical role for 14-3-3τ in promoting breast cancer metastasis, in part through binding to and inhibition of RhoGDIα, a negative regulator of Rho GTPases and a metastasis suppressor. 14-3-3τ binds Ser174-phosphorylated RhoGDIα and blocks its association with Rho GTPases, thereby promoting epidermal growth factor (EGF)-induced RhoA, Rac1, and Cdc42 activation. When 14-3-3τ is overexpressed in MCF7 breast cancer cells that express 14-3-3τ at low levels, it increases motility, reduces adhesion, and promotes metastasis in mammary fat pad xenografts. On the other hand, depletion of 14-3-3τ in MCF7 cells and in an invasive cell line, MDA-MB231, inhibits Rho GTPase activation and blocks breast cancer migration and invasion. Moreover, 14-3-3τ 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 14-3-3τ in breast cancer progression. Our work indicates that 14-3-3τ is a novel therapeutic target to prevent breast cancer metastasis.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Lin
authors.forename: Shi
authors.initials: S
authors.lastname: Ke
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Lin
authors.forename: Fang-Tsyr
authors.initials: FT
authors.lastname: Lin
authors.forename: Weei-Chin
authors.initials: WC
authors.lastname: Lin
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D020741:rho GTP-Binding Proteins