title: Egr-1 enhances drug resistance of breast cancer by modulating MDR1 expression in a GGPPS-independent manner.
abstract: The multidrug resistance 1 (MDR1) gene product P-glycoprotein is an ATP-dependent efflux pump associated with chemotherapy failure in breast cancer. In the present study, we show that paclitaxel induces MDR1 expression in the MCF-7 breast cancer cell line in a MAPK/Egr-1-dependent manner. Paclitaxel exposure activated the Erk1/2/MAPK pathway and promoted the accumulation of the early response transcription factor Egr-1 in MCF-7 cells. Egr-1 binds to the GC element on the proximal MDR1 promoter to enhance MDR1 transcription. Loss of Egr-1 function in paclitaxel-resistant MCF-7 cells decreased MDR1 expression, whereas inhibiting Erk1/2 activity reduced both Egr-1 accumulation and MDR1 expression. These findings suggest that Erk1/2-induced Egr-1 accumulation activates MDR1 transcription and thereby induces the drug resistance observed in paclitaxel-resistant MCF-7 cells. Further mechanistic studies indicate that Egr-1 most likely does not induce the constitutive activation of Erk1/2 through its target gene geranylgeranyl diphosphate synthase (GGPPS), which regulates Ras prenylation. Indeed, our results suggest a novel pathway by which paclitaxel induces MDR1 expression, possibly illuminating a potential target pathway for the prevention of MDR1-mediated drug resistance.
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tao
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Shi
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Sun
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy; D004122:Dimethylallyltranstransferase / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000378:metabolism / Q000502:physiology*; D051231:Farnesyltranstransferase / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051228:Geranyltranstransferase / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D004122:Dimethylallyltranstransferase; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase; C495427:GGPS1 protein, human; D017239:Paclitaxel