title: Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells.
abstract: Human epidermal growth factor receptor 2 (HER2/neu, also known as ErbB2) overexpression is correlated with the poor prognosis and chemoresistance in cancer. Breast cancer resistance protein (BCRP and ABCG2) is a drug efflux pump responsible for multidrug resistance (MDR) in a variety of cancer cells. HER2 and BCRP are associated with poor treatment response in breast cancer patients, although the relationship between HER2 and BCRP expression is not clear. Here, we showed that transfection of HER2 into MCF7 breast cancer cells (MCF7/HER2) resulted in an up-regulation of BCRP via the phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-κB) signaling. Treatment of MCF/HER2 cells with the PI3K inhibitor LY294002, the IκB phosphorylation inhibitor Bay11-7082, and the dominant negative mutant of IκBα inhibited HER2-induced BCRP promoter activity. Furthermore, we found that HER2 overexpression led to an increased resistance of MCF7 cells to multiple antitumor drugs such as paclitaxel (Taxol), cisplatin (DDP), etoposide (VP-16), adriamycin (ADM), mitoxantrone (MX), and 5-fluorouracil (5-FU). Moreover, silencing the expression of BCRP or selectively inhibiting the activity of Akt or NF-κB sensitized the MCF7/HER2 cells to these chemotherapy agents at least in part. Taken together, up-regulation of BCRP through PI3K/AKT/NF-κB signaling pathway played an important role in HER2-mediated chemoresistance of MCF7 cells, and AKT, NF-κB, and BCRP pathways might serve as potential targets for therapeutic intervention.
authors.affiliation: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou 510182, China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Meilin
authors.initials: M
authors.lastname: Feng
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt