An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells

Cancer Cell. 2004 Nov;6(5):497-506. doi: 10.1016/j.ccr.2004.09.032.

Abstract

Autocrine Wnt signaling in the mouse mammary tumor virus model was the first identified mechanism of canonical pathway activation in cancer. In search of this transformation mechanism in human cancer cells, we identified breast and ovarian tumor lines with upregulation of the uncomplexed transcriptionally active form of beta-catenin without mutations afflicting downstream components. Extracellular Wnt antagonists FRP1 and DKK1 caused a dramatic downregulation of beta-catenin levels in these tumor cells associated with alteration of biological properties and increased expression of epithelial differentiation markers. Colorectal carcinoma cells with knockout of the mutant beta-catenin allele retained upregulated beta-catenin levels, which also could be inhibited by these Wnt antagonists. Together, these findings establish the involvement of autocrine Wnt signaling in human cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Autocrine Communication / drug effects
  • Breast Neoplasms / metabolism
  • Cell Cycle Proteins / pharmacology
  • Colonic Neoplasms
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Leucine-Responsive Regulatory Protein
  • Neoplasms / metabolism*
  • Ovarian Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases / pharmacology
  • Proteins / pharmacology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Signal Transduction
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Wnt Proteins
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DKK1 protein, human
  • DNA-Binding Proteins
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Leucine-Responsive Regulatory Protein
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases