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: Yang Xiao, Vivian Y Lin, Shi Ke, Gregory E Lin, Fang-Tsyr Lin, Weei-Chin Lin
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 34 Issue 14 Pg. 2635-49 (Jul 2014) ISSN: 1098-5549 [Electronic] United States
• PMID: 24820414 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 14-3-3 Proteins
• rho Guanine Nucleotide Dissociation Inhibitor alpha
• rho GTP-Binding Proteins

Topics

• 14-3-3 Proteins (genetics, metabolism)
• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Adhesion
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• MCF-7 Cells
• Mammary Neoplasms, Experimental
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis (genetics, pathology)
• Phosphorylation
• Signal Transduction
• rho GTP-Binding Proteins (metabolism)
• rho Guanine Nucleotide Dissociation Inhibitor alpha (metabolism)