title: HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.
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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: 1] Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA [2] Department of Nanobiomedical Science and BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Nanobiomedical Science and BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jang
authors.affiliation: 1] Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA [2] Department of Nanobiomedical Science and BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
authors.forename: Yeon-Sun
authors.initials: YS
authors.lastname: Seong
authors.affiliation: 1] Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA [2] Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20057, USA [3] Department of Nanobiomedical Science and BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D010269:Paraquat / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D004317:Doxorubicin; D051547:Heme Oxygenase-1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D010269:Paraquat; D018719:Erb-b2 Receptor Tyrosine Kinases; C120809:ABCC5 protein, human; C495635:NFE2L2 protein, human; C496541:HMOX1 protein, human; C508053:ERBB2 protein, human