MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells

J Biol Chem. 2012 Mar 23;287(13):10703-10713. doi: 10.1074/jbc.M111.323311. Epub 2012 Feb 8.

Abstract

MUC1 is a heterodimeric glycoprotein that is overexpressed in breast cancers. The present studies demonstrate that the oncogenic MUC1 C-terminal subunit (MUC1-C) associates with the TCF7L2 transcription factor. The MUC1-C cytoplasmic domain (MUC1-CD) binds directly to the TCF7L2 C-terminal region. MUC1-C blocks the interaction between TCF7L2 and the C-terminal-binding protein (CtBP), a suppressor of TCF7L2-mediated transcription. TCF7L2 and MUC1-C form a complex on the cyclin D1 gene promoter and MUC1-C promotes TCF7L2-mediated transcription by the recruitment of β-catenin and p300. Silencing MUC1-C in human breast cancer cells down-regulated activation of the cyclin D1 promoter and decreased cyclin D1 expression. In addition, a MUC1-C inhibitor blocked the interaction with TCF7L2 and suppressed cyclin D1 levels. These findings indicate that the MUC1-C oncoprotein contributes to TCF7L2 activation and thereby promotes cyclin D1 expression in breast cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cyclin D1 / biosynthesis*
  • Cyclin D1 / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factor 7-Like 2 Protein / metabolism*
  • Transcription, Genetic*
  • beta Catenin / genetics
  • beta Catenin / metabolism
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • CCND1 protein, human
  • DNA-Binding Proteins
  • MUC1 protein, human
  • Mucin-1
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin
  • Cyclin D1
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • p300-CBP Transcription Factors