E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-tomesenchymal transition in breast cancer cell lines

Abstract

Using genome-wide expression profiling of a panel of 27 human mammary cell lines with different mechanisms of E-cadherin inactivation, we evaluated the relationship between E-cadherin status and gene expression levels. Expression profiles of cell lines with E-cadherin (CDHI) promoter methylation were significantly different from those with CDHI expression or, surprisingly, those with CDHI truncating mutations. Furthermore, we found no significant differentially expressed genes between cell lines with wild-type and mutated CDHI. The expression profile complied with the fibroblastic morphology of the cell lines with promoter methylation, suggestive of epithelial-mesenchymal transition (EMT). All other lines, also the cases with CDHI mutations, had epithelial features. Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDHI promoter methylation, a fibroblastic phenotype and expression profile. We suggest that CDHI promoter methylation, but not mutational inactivation, is part of an entire programme, resulting in EMT and increased invasiveness in breast cancer. The molecular events that are part of this programme can be inferred from the differentially expressed genes and include genes from the TGFβ pathway, transcription factors involved in CDHI regulation (i.e. ZFHXIB, SNAI2, but not SNAII, TWIST), annexins, API/2 transcription factors and members of the actin and intermediate filament cytoskeleton organisation. © 2006 Cancer Research UK.