Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires ?-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways.

ABSTRACT: Perturbations in the adipocytokine profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1), and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of ?-catenin leading to increased promoter recruitment. Silencing of ?-catenin or treatment with the small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion, and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3? (GSK3?) via Akt activation resulting in a substantial decrease in the formation of the GSK3?-LKB1-Axin complex that leads to increased accumulation of ?-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3? phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3? phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of the Wnt/?-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3? phosphorylation, and ?-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3?, and vimentin along with higher nuclear accumulation of ?-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized cross-talk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.

SUBMITTER: Yan D 

PROVIDER: S-EPMC3318705 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature