Investigation of the role of DNA methylation in the expression of ERBB2 in human myocardium.

The ERBB2 gene encodes a transmembrane tyrosine kinase receptor that belongs to the epidermal growth factor receptor (EGFR) family. ERBB2 plays a pivotal role during heart development and is essential for normal cardiac function, particularly during episodes of cardiac stress. The monoclonal antibody drug trastuzumab is used for the therapy of breast cancers that overexpress ERBB2. The clinical use of trastuzumab is limited by the development of cardiotoxicity in some patients. Inter-individual differences in the expression of ERBB2 in cardiac tissue may impact the risk of cardiotoxicity. In this study, we examined whether DNA methylation status in the proximal promoter region of ERBB2 is associated to variable ERBB2 mRNA and ERBB2 protein expression in human myocardium. Complementary studies with ERBB2 gene reporter constructs and chromatin immunoprecipitation suggest that differential methylation in specific CpG sites modify the binding of Sp1 to the promoter of ERBB2. DNA methylation in the ERBB2 locus may contribute to the variable expression of ERBB2 in human myocardium.