title: let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer.
abstract: MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER-α66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-α36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-α36 3'UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-α36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-α36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB-231. The reverse correlation between let-7 miRNAs and ER-α36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-α36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-α36 constructs without 3'UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-α36 mediated nongenomic estrogen signal pathways and Tam resistance.
authors.affiliation: Genomics and Functional Proteomics Laboratories, Osteoporosis Research Center, Omaha, Nebraska, United States of America.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Caishu
authors.initials: C
authors.lastname: Deng
authors.forename: Weida
authors.initials: W
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.forename: Danjun
authors.initials: D
authors.lastname: Ma
authors.forename: Mingxi
authors.initials: M
authors.lastname: Guo
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.forename: Zhaoyi
authors.initials: Z
authors.lastname: Wang
authors.forename: Gary Guishan
authors.initials: GG
authors.lastname: Xiao
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human; C487931:mirnlet7 microRNA, human; C508053:ERBB2 protein, human