Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements

Oncogene. 1999 Dec 2;18(51):7274-9. doi: 10.1038/sj.onc.1203336.


Inactivation of the E-cadherin cell adhesion molecule is believed critical in the development and behavior of many epithelial cancers, though mutations in the E-cadherin gene account for inactivation in only a fraction of cases. In many breast cancer lines, E-cadherin transcription is extinguished, but the role and significance of alterations in trans-acting transcription factors, promoter hypermethylation, and chromatin changes remain unresolved. To gain further insights into mechanisms underlying E-cadherin inactivation in breast cancer, we analysed somatic cell hybrids resulting from pairwise fusions between breast cancer lines with intact E-cadherin transcription (E-cad+) and lines lacking E-cadherin transcription (E-cad-). All hybrid lines failed to express E-cadherin transcripts and protein, despite the fact that E-cadherin alleles from E-cad+ lines were present in the hybrids. Elements in the proximal 108 bp of the E-cadherin promoter, when present in reporter gene constructs, were sufficient to direct strong transcription in E-cad+ breast lines, but displayed weak activity in E-cad- parental lines and hybrids. E-cadherin expression could not be restored in E-cad- lines or hybrids by treatment with a DNA demethylating agent and/or a histone deacetylase inhibitor. Our findings suggest loss of E-cadherin expression in some breast cancers may be due to dominant repression of the trans-acting pathways that regulate E-cadherin transcription.

Publication types

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

MeSH terms

  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cadherins / biosynthesis
  • Cadherins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic / genetics*
  • Transcription Factors / genetics
  • Tumor Cells, Cultured


  • Cadherins
  • Transcription Factors