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YWHAZ

ErbB2, a metastasis-promoting oncoprotein, is overexpressed in approximately 25% of invasive/metastatic breast cancers, but in 50%-60% of noninvasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3zeta in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3zeta overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3zeta overexpression reduced cell adhesion by activating the TGF-beta/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition. Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3zeta had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.

Loss of 14-3-3sigma has been observed in multiple tumor types; however, the mechanisms by which 14-3-3sigma loss leads to tumor progression are not understood. The experiments in this report demonstrate that loss of 14-3-3sigma leads to a decrease in the expression of epithelial markers and an increase in the expression of mesenchymal markers, which is indicative of an induction of the epithelial to mesenchymal transition (EMT). The EMT was accompanied by an increase in migration and invasion in the 14-3-3sigma(-/-) cells. 14-3-3sigma(-/-) cells show increased stabilization of c-Jun, resulting in an increase in the expression of the EMT transcription factor slug. 14-3-3sigma induces the ubiquitination and degradation of c-Jun in an FBW7-dependent manner. c-Jun ubiquitination is dependent on the presence of an intact nuclear export pathway as c-Jun is stabilized and localized to the nucleus in the presence of a nuclear export inhibitor. Furthermore, the absence of 14-3-3sigma leads to the nuclear accumulation and stabilization of c-Jun, suggesting that 14-3-3sigma regulates the subcellular localization of c-Jun. Our results have identified a novel mechanism by which 14-3-3sigma maintains the epithelial phenotype by inhibiting EMT and suggest that this property of 14-3-3sigma might contribute to its function as a tumor suppressor gene.CI - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.