1. ¹Department of Pathology, Leiden University Medical Center, PO Box 9600, L1-Q, NL-2300 RC Leiden, The Netherlands
2. ²Medical Statistics, Leiden University Medical Center, PO Box 9604, NL-2300 RC Leiden, The Netherlands
3. ³Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, NL-2300 RA Leiden, The Netherlands

Correspondence: Dr A-M Cleton-Jansen, E-mail: A.M.Cleton-Jansen@lumc.nl

Revised 13 January 2006; Accepted 18 January 2006; Published online 21 February 2006.

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 (CDH1) promoter methylation were significantly different from those with CDH1 expression or, surprisingly, those with CDH1 truncating mutations. Furthermore, we found no significant differentially expressed genes between cell lines with wild-type and mutated CDH1. 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 CDH1 mutations, had epithelial features. Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDH1 promoter methylation, a fibroblastic phenotype and expression profile. We suggest that CDH1 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 TGF pathway, transcription factors involved in CDH1 regulation (i.e. ZFHX1B, SNAI2, but not SNAI1, TWIST), annexins, AP1/2 transcription factors and members of the actin and intermediate filament cytoskeleton organisation.