Transcriptional defects underlie loss of E-cadherin expression in breast cancer.
Decreased expression of E-cadherin (E-cad), a calcium-dependent cell adhesion molecule, has been seen in many different epithelial cancers. Although somatic mutations in the E-cad gene have been identified in a small subset of tumors, in the majority of cancers, the mechanisms underlying loss of E-cad expression are poorly understood. We have cloned the human E-cad promoter and defined its critical components in functional assays. In eight human breast cancer cell lines, there was a striking correlation between endogenous E-cad gene expression and E-cad promoter activity observed following the introduction of reporter gene constructs into the lines. These and other observations suggest that defects in trans-acting pathways regulation E-cad expression are the primary basis for the loss of its expression in most breast cancers. The results have significant implications for understanding the gene expression differences that underlie tumor heterogeneity and progression events in breast and other epithelial cancers.
Ji
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Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0638, USA.
Woodard
A S
AS
Rimm
D L
DL
Fearon
E R
ER
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics*; D015820:Cadherins / Q000032:analysis / Q000235:genetics*; D003001:Cloning, Molecular; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D000077209:Decitabine; D001374:Azacitidine