CDH1promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer

Abstract

BackgroundThe E-cadherin gene (CDH1) maps, at chromosome 16q22.1, a region often associated with loss of heterozygosity (LOH) in human breast cancer. LOH at this site is thought to lead to loss of function of this tumor suppressor gene and was correlated with decreased disease-free survival, poor prognosis, and metastasis. Differential CpG island methylation in the promoter region of the CDH1 gene might be an alternative way for the loss of expression and function of E-cadherin, leading to loss of tissue integrity, an essential step in tumor progression.MethodsThe aim of our study was to assess, by Methylation-Specific Polymerase Chain Reaction (MSP), the methylation pattern of the CDH1 gene and its possible correlation with the expression of E-cadherin and other standard immunohistochemical parameters (Her-2, ER, PgR, p53, and K-67) in a series of 79 primary breast cancers (71 infiltrating ductal, 5 infiltrating lobular, 1 metaplastic, 1 apocrine, and 1 papillary carcinoma).ResultsCDH1 hypermethylation was observed in 72% of the cases including 52/71 ductal, 4/5 lobular carcinomas and 1 apocrine carcinoma. Reduced levels of E-cadherin protein were observed in 85% of our samples. Although not statistically significant, the levels of E-cadherin expression tended to diminish with the CDH1 promoter region methylation. In the group of 71 ductal cancinomas, most of the cases of showing CDH1 hypermethylation also presented reduced levels of expression of ER and PgR proteins, and a possible association was observed between CDH1 methylation and ER expression (p = 0.0301, Fisher's exact test). However, this finding was not considered significant after Bonferroni correction of p-value.ConclusionOur preliminary findings suggested that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression in a subgroup of cases characterized by loss of expression of other important genes to the mammary carcinogenesis process, probably due to the disruption of the mechanism of maintenance of DNA methylation in tumoral cells.

Loss of Expression and Aberrant Methylation of the CDH1 (E-cadherin) Gene in Breast Cancer Patients from Kashmir

“…In these cases, methylation specific PCR fragment might be the result of contamination with infiltrating leukocytes, making the detection and interpretation of tumor-associated distorted methylation patterns more complicated (Lombaerts et al, 2004). Overall, our data corroborate the findings reported by earlier studies that CDH1 promoter hypermethylation is responsible for its heterogeneous downregulation in ductal cell carcinoma (Graff et al, 2000;Caldeira et al, 2006;Prasad et al, 2008).…”

“…The frequency of CDH1 methylation in our study is similar to other studies conducted on breast cancer patients (Shinozaki et al, 2005;Prasad et al, 2008). Other previous studies have shown varying frequencies of CDH1 methylation viz; 72% (Caldeira et al, 2006), 26.1% (Hu et al, 2002) , 21.7% (Sebova et al, 2011), 94% (Shargh et al, 2011) in breast cancer tissues from different population. The comparison of normal and malignant tissues showed a statistically significant (p<0.0001) difference in the methylation pattern, thus there was significanteightfold increase in the risk to breast cancer in the subjects with methylated CDH1 promoter.…”

“…Our results of hormone receptor positivity are almost similar to an earlier investigation conducted on the breast cancer patients from Kashmir (Sofi et al, 2012). However, we did not find any correlation between methylation of CDH1 and estrogen or progesterone receptor status although previous studies have reported such associations (Shinozaki et al, 2005;Caldeira et al, 2006;Li et al, 2006;Ronneberg et al, 2011).…”

“…Reduced expression of E-cadherin is regarded as one of the main molecular events involved in the dysfunction of the cell-cell adhesion system, triggering cancer invasion and metastasis (Debies and Welch, 2001). Hypermethylation in CDH1 gene and its reduced expression in gut, lung, prostate and breast cancers, which could be due to the disruption of intercellular adhesion and impairment of β-catenin mediated transactivation of cadherin-catenin complex (Graff et al, 1995;Sadot et al, 1998;Tamura et al, 2000;Hu et al, 2002;Caldeira et al, 2006;Prasad et al, 2008;Zheng et al, 2012) has been reported.…”

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…CDH1 at 16q22 has been reported as the major candidate gene and is often methylated [40] but do not fulfill our selection criteria. However, PRMT7 coding for an arginine methyltransferase, with unknown relation to cancer prognosis, is additionally upregulated (supplementary Fig.…”