E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas.
Expression of the Ca(2+)-dependent, homotypic cell:cell adhesion molecule, E-cadherin (E-cad), suppresses tumor cell invasion and metastasis in experimental tumor models. Decreased E-cad expression is common in poorly differentiated, advanced-stage carcinomas. These data implicate E-cad as an "invasion suppressor" gene. The mechanism by which E-cad is silenced in advanced stage carcinomas is unclear. In this report, we show that: (a) the 5' CpG island of E-cad is densely methylated in E-cad-negative breast and prostate carcinoma cell lines and primary breast carcinoma tissue but is unmethylated in normal breast tissue; (b) treatment with the demethylating agent, 5-aza-2'-deoxycytidine, partially restores E-cad RNA and protein levels in E-cad-negative breast and prostate carcinoma cell lines; and (c) and E-cad promoter/CAT construct is expressed in both E-cad-positive and -negative breast and prostate carcinoma cell lines, indicating that these cells have the active transcriptional machinery necessary for E-cad expression. Our data demonstrate that frequent loss of E-cad expression in human breast and prostate carcinomas results from hypermethylation of the E-cad promoter region.
Graff
J R
JR
Johns Hopkins Oncology Center, Johns Hopkins University Medical Center, Baltimore, Maryland 21231, USA.
Herman
J G
JG
Lapidus
R G
RG
Chopra
H
H
Xu
R
R
Jarrard
D F
DF
Isaacs
W B
WB
Pitha
P M
PM
Davidson
N E
NE
Baylin
S B
SB
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D004247:DNA / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008745:Methylation; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D015820:Cadherins; D004247:DNA