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

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 β-catenin leading to increased promoter recruitment. Silencing of β-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 3β (GSK3β) via Akt activation resulting in a substantial decrease in the formation of the GSK3β-LKB1-Axin complex that leads to increased accumulation of β-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3β phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3β 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/β-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3β phosphorylation, and β-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3β, and vimentin along with higher nuclear accumulation of β-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.

Pubmed ID: 22270359


  • Yan D
  • Avtanski D
  • Saxena NK
  • Sharma D


The Journal of biological chemistry

Publication Data

March 9, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: K01DK076742
  • Agency: NCI NIH HHS, Id: R01 CA131294
  • Agency: NCI NIH HHS, Id: R01CA131294
  • Agency: NIDDK NIH HHS, Id: R03DK089130

Mesh Terms

  • Bicyclo Compounds, Heterocyclic
  • Breast Neoplasms
  • Cadherins
  • Cell Line, Tumor
  • Cell Nucleus
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3
  • Histone Deacetylases
  • Humans
  • Leptin
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • Pyrimidinones
  • Repressor Proteins
  • Vimentin
  • Wnt Signaling Pathway
  • Wnt1 Protein
  • beta Catenin