E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines.
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 TGFbeta 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.
Department of Pathology, Leiden University Medical Center, PO Box 9600, L1-Q, NL-2300 RC Leiden, The Netherlands.
M
M
Lombaerts
T
T
van Wezel
K
K
Philippo
J W F
JW
Dierssen
R M E
RM
Zimmerman
J
J
Oosting
R
R
van Eijk
P H
PH
Eilers
B
B
van de Water
C J
CJ
Cornelisse
A-M
AM
Cleton-Jansen
D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D004847:Epithelial Cells; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology
D015820:Cadherins; D016212:Transforming Growth Factor beta