title: MiR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3.
abstract: MiR-27b downregulation is significantly associated with tamoxifen resistance in breast cancer cells. However, how it is downregulated in tamoxifen resistant (TamR) breast cancer cells and its downstream regulation were not clear. By performing MSP assay and QRT-PCR analysis with the use of 5-AZA-dC, a DNA methyltransferase inhibitor, we observed that TamR MCF-7 cells had significantly higher levels of methylation in the miR-27b promoter region than tamoxifen sensitive MCF-7 (TamS) cells and demethylation restored miR-27b expression. Re-expression of miR-27b sensitized TamR MCF-7 cells to tamoxifen, inhibited invasion and reversed epithelial-mesenchymal transition (EMT)-like properties. By using bioinformatics analysis and following dual luciferase and western blot analysis, this study confirmed a direct regulation of miR-27b on HMGB3 expression by binding to the 3'UTR. In addition, this study also found that silencing of HMGB3 indeed partially phenocopied the effects of miR-27b in reducing tamoxifen resistance and cell invasion and in reversing EMT-like properties. Therefore, we infer that HMGB3 is a functional target of miR-27b in modulation of tamoxifen resistance and EMT.
authors.affiliation: Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100006, China.
authors.forename: Xiunan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100006, China. Electronic address: yumeiwu1@163.com.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100006, China.
authors.forename: Aihui
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D025765:HMGB3 Protein / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D025765:HMGB3 Protein; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D013629:Tamoxifen
keywords: HMGB3; MiR-27b; Promoter methylation; Tamoxifen