Abstract
HER2 receptor tyrosine kinase (encoded by the ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (HER2-positive breast cancers). Resistance to HER2-targeting therapies is partially due to the loss of HER2 expression in tumor cells during treatment. However, little is known about the exact mechanism of HER2 downregulation in HER2-positive tumor cells. Here, by analyzing publicly available genomic data we investigate the hypothesis that epithelial-mesenchymal transition (EMT) abrogates HER2 expression by epigenetic silencing of the ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. As result, HER2 expression was found to be positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes, respectively. The ERBB2 chromatin of HER2-high epithelial-like breast cancer cells and HER2-low mesenchymal-like cells were found to be open/active and closed/inactive, respectively. Decreased HER2 expression was correlated with increased EMT phenotype, inactivated chromatin and lower response to lapatinib. We also found that induction of EMT in the HER2-positive breast cancer cell line BT474 resulted in downregulated HER2 expression and reduced trastuzumab binding. Our results suggest that ERBB2 gene silencing by epigenetic regulation during EMT may be a mechanism of de novo resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.
Highlights
The HER2 receptor tyrosine kinase is a 1255 amino acid transmembrane epidermal growth factor receptor with tyrosine kinase activity and a molecular weight of 185 kDa [1,2]
To investigate whether the expression level of the ERBB2 gene is correlated with the expression of epithelialmesenchymal transition (EMT) marker genes, we analyzed the RNA-seq expression of the ERBB2 gene, 12 epithelial marker genes (ALCAM, CD24, CDH1, F11R, FOXA1, KRT7, KRT8, KRT18, KRT19, MUC, NECTIN2, NECTIN4) as well as 12 mesenchymal marker genes (CD44, CTNNB1, FOXC1, MYC, NOTCH1, NOTCH2, SNAI2, SOX10, TWIST2, VIM, ZEB1, ZEB2) in 1904 breast cancer tumor samples included in a METABRIC study [24]
We used cBioPortal portal [20] to investigate correlations between the mRNA levels of ERBB2 and the EMT markers in each tumor sample. These results showed that the expression of the ERBB2 gene was positively and negatively correlated with the expression of the epithelial phenotype (Figure 1A) and the mesenchymal phenotype (Figure 1B) marker genes, respectively
Summary
The HER2 receptor tyrosine kinase (encoded by the ERBB2 gene) is a 1255 amino acid transmembrane epidermal growth factor receptor with tyrosine kinase activity and a molecular weight of 185 kDa [1,2]. HER2 contains four extracellular domains (ECD; domains I-IV; amino acids 1–641), an extracellular juxtamembrane region (EJM; amino acids 642–652) a transmembrane domain (TM; amino acids 653–675), an intracellular juxtamembrane region (IJM; amino acids 676–730), an intracellular tyrosine kinase domain (TK; amino acids 731–906), and a C-terminal tail (amino acids 907–1255) [3,4,5,6]. HER2 dimerization causes activation of its kinase domain which phosphorylates downstream mediators and promotes the receptor tyrosine kinase signaling cascades (PI3K/Akt, PLC-È and MAPK pathways). HER2 overexpression results in over-activation of downstream PI3K/Akt, PLC-È and MAPK pathways leading to increased tumor cell growth, survival, motility, and invasion [10]
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