Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 34, Issue 14, Pages 2635-2649Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00076-14
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Funding
- Department of Defense Breast Cancer Research Program [W81XWH-09-1-0338]
- National Institutes of Health [RO1CA100857, RO1CA138641, ARRA 3 P30CA125123-03S5]
- NIH [NCI P30CA125123]
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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.
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