CDH1 (E-cadherin) Gene Methylation in Human Breast Cancer: Critical Appraisal of a Long and Twisted Story

SIMPLE SUMMARY: Genes can be inactivated by specific modifications of DNA bases, most often by adding a methyl group to the DNA base cytosine if it is followed by guanosine (CG methylation). This modification prevents gene expression and has been reported for many different genes in nearly all types of cancer. A prominent example is the gene CDH1, which encodes the cell-adhesion molecule E-cadherin. This is an important player in the spreading of tumor cells within the body (metastasis). Particularly in human breast cancer, many different research groups have studied the inactivation of the CDH1 gene via DNA methylation using various methods. Over the last 20 years, different, in part, even contradicting results have been published for the CDH1 gene in breast cancer. This review summarizes the most important publications and explains the bewildering heterogeneity of results through careful analysis of the methods which have been used. ABSTRACT: Epigenetic inactivation of a tumor suppressor gene by aberrant DNA methylation is a well-established defect in human tumor cells, complementing genetic inactivation by mutation (germline or somatic). In human breast cancer, aberrant gene methylation has diagnostic, prognostic, and predictive potential. A prominent example is the hypermethylation of the CDH1 gene, encoding the adhesion protein E-Cadherin (“epithelial cadherin”). In numerous publications, it is reported as frequently affected by gene methylation in human breast cancer. However, over more than two decades of research, contradictory results concerning CDH1 gene methylation in human breast cancer accumulated. Therefore, we review the available evidence for and against the role of DNA methylation of the CDH1 gene in human breast cancer and discuss in detail the methodological reasons for conflicting results, which are of general importance for the analysis of aberrant DNA methylation in human cancer specimens. Since the loss of E-cadherin protein expression is a hallmark of invasive lobular breast cancer (ILBC), special attention is paid to CDH1 gene methylation as a potential mechanism for loss of expression in this special subtype of human breast cancer. Proper understanding of the methodological basis is of utmost importance for the correct interpretation of results supposed to demonstrate the presence and clinical relevance of aberrant DNA methylation in cancer specimens.