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Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression.

Slug (Snail2) plays critical roles in regulating the epithelial-mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled remain unclear. Herein we identify an unrecognized canonical Wnt/GSK3β/β-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3β and subsequently undergoes β-Trcp1-dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3β kinase activity is inhibited, nuclear Slug levels increase, and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels, and reduced expression of the tumor suppressor Breast Cancer 1, Early Onset (BRCA1), further studies demonstrate that Slug-as well as Snail-directly represses BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients. Together, these findings establish unique functional links between canonical Wnt signaling, Slug expression, EMT, and BRCA1 regulation.

Pubmed ID: 23011797


  • Wu ZQ
  • Li XY
  • Hu CY
  • Ford M
  • Kleer CG
  • Weiss SJ


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 9, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA107469
  • Agency: NCI NIH HHS, Id: CA116516
  • Agency: NCI NIH HHS, Id: CA125577
  • Agency: NCI NIH HHS, Id: CA154224
  • Agency: NIDDK NIH HHS, Id: P60 DK020572
  • Agency: NCI NIH HHS, Id: R01 CA107469
  • Agency: NCI NIH HHS, Id: R01 CA125577

Mesh Terms

  • Amino Acid Sequence
  • BRCA1 Protein
  • Blotting, Western
  • Breast Neoplasms
  • Cell Line, Tumor
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3
  • HEK293 Cells
  • Histone Demethylases
  • Histones
  • Humans
  • Immunohistochemistry
  • MCF-7 Cells
  • Methylation
  • Molecular Sequence Data
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Transcription Factors
  • Ubiquitination
  • Wnt Signaling Pathway