Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements.
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.
Hajra
K M
KM
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109 USA.
Ji
X
X
Fearon
E R
ER
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D015820:Cadherins; D014157:Transcription Factors