title: A Bmi1-miRNAs cross-talk modulates chemotherapy response to 5-fluorouracil in breast cancer cells.
abstract: The polycomb group transcriptional modifier Bmi1 is often upregulated in numerous cancers and is intensely involved in normal and cancer stem cells, and importantly is as a prognostic indicator for some cancers, but its role in breast cancer remains unclear. Here, we found Bmi1 overexpression in 5-Fu (5-fluorouracil)-resistant MCF-7 cells (MCF-7/5-Fu) derived from MCF-7 breast cancer cells, MDA-MB-231 and MDA-MB-453 breast cancer cells compared to MCF-7 cells, was related with 5-Fu resistance and enrichment of CD44(+)/CD24(-) stem cell subpopulation. Bmi1 knockdown enhanced the sensitivity of breast cancer cells to 5-Fu and 5-Fu induced apoptosis via mitochondrial apoptotic pathway, and decreased the fraction of CD44(+)/CD24(-) subpopulation. In addition, our analysis showed inverse expression pattern between Bmi1 and miR-200c and miR-203 in selected breast cancer cell lines, and miR-200c and miR-203 directly repressed Bmi1 expression in protein level confirmed by luciferase reporter assay. MiR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1. Inversely, Bmi1 overexpression inhibited miR-200c expression in MCF-7 cells, but not miR-203, however ectopic wild-type p53 expression reversed Bmi1 mediated miR-200c downregulation, suggesting the repressive effect of Bmi1 on miR-200c maybe depend on p53. Thus, our study suggests a cross-talk between Bmi1 and miR-200c mediated by p53, and Bmi1 interference would improve chemotherapy efficiency in breast cancer via susceptive apoptosis induction and cancer stem cell enrichment inhibition.
authors.affiliation: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P. R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yin
authors.forename: Guopei
authors.initials: G
authors.lastname: Zheng
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Jia
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; C069077:BMI1 protein, human; C533896:MIRN200 microRNA, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D063150:Polycomb Repressive Complex 1; D005472:Fluorouracil
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