Journal
LIFE-BASEL
Volume 11, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/life11090868
Keywords
epithelial-mesenchymal transition; HER2; ERBB2; breast cancer; epigenetics; trastuzumab
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- Graduate Studentship from Women and Children's Health Research Institute (WCHRI)
- CIHR
- WCHRI
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HER2 receptor tyrosine kinase is overexpressed in 25% of breast cancer tumors. Resistance to HER2-targeting therapies may be due to epigenetic silencing of the ERBB2 gene during epithelial-mesenchymal transition, leading to decreased HER2 expression and lower response to lapatinib and trastuzumab in HER2-positive breast cancer cells.
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.
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