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Abstract
Overexpression and/or activation of HER2 confers resistance of cancer cells to chemotherapeutic drugs. NRF2 also gives drug resistance of cancer cells through induction of detoxification and/or drug efflux proteins. Although several upstream effectors of NRF2 overlapped with the downstream molecules of HER2 pathway, no direct link between HER2 and NRF2 has ever been established. Here, we identified that co-expression of a constitutively active HER2 (HER2CA) and NRF2 increased the levels of NRF2 target proteins, HO-1 and MRP5. We also identified HER2CA activated the DNA-binding of NRF2 and the antioxidant response element (ARE)-mediated transcription in an NRF2-dependent manner. In addition, NRF2 and HER2CA cooperatively up-regulated the mRNA expression of various drug-resistant and detoxifying enzymes including GSTA2, GSTP1, CYP3A4, HO-1, MRP1, and MRP5. We also demonstrated that NRF2 binds to HER2 not only in transiently transfected HEK293T cells but also in HER2-amplified breast cancer cells. Functionally, overexpression of HER2CA gave resistance of MCF7 breast cancer cells to either paraquat or doxorubicin. Overexpression of dominant negative NRF2 (DN-NRF2) reduced the HER2CA-induced resistance of MCF7 cells to these agents. Taken together, these results suggest that active HER2 binds and regulates the NRF2-dependent transcriptional activation and induces drug resistance of cancer cells.
Highlights
HER2 confers drug resistance of human breast cancer cells through activation of Nuclear factor erythroid 2-related factor 2 (NRF2) by direct interaction
We identified that co-expression of a constitutively active HER2 (HER2CA) and NRF2 increased the levels of NRF2 target proteins, heme oxygenase-1 (HO-1) and multidrug-resistant protein 5 (MRP5)
We performed transient transfection of FLAG-NRF2 in the absence or presence of constitutively active HER2 (HER2CA)[30] in MCF7 cells, and the expression of proteins were analyzed by western blot analysis
Summary
Overexpression of dominant negative NRF2 (DN-NRF2) reduced the HER2CA-induced resistance of MCF7 cells to these agents Taken together, these results suggest that active HER2 binds and regulates the NRF2-dependent transcriptional activation and induces drug resistance of cancer cells. It has been reported that HER2 up-regulates the expression of the breast cancer resistance protein (BCRP)[5] through interaction with EGFR to render resistance to aromatase inhibitors[6] In these cases the HER2-mediated signal transduction, such as the PI3K/AKT pathway, is suggested as the basis of HER2-mediated drug resistance[7]. We demonstrated that HER2 activates NRF2 transcriptional activity through direct protein-protein interaction and induces a subset of NRF2-target gene expression in human breast cancer cells
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