title: MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis.
abstract: MicroRNAs (miRNA) are small non-coding RNAs that regulate the expression of approximately 60% of all human genes and play important roles in disease processes. Recent studies have demonstrated a link between dysregulated expression of miRNAs and breast carcinogenesis. Long-term estrogen exposure is implicated in development of human breast cancers, yet underlying mechanisms remain elusive. We have recently demonstrated that antioxidant vitamin C (vit C) prevents estrogen-induced breast tumor development. In this study, we investigated the role of vit C in the regulation of microRNA-93 (miR-93) and its target gene(s) in a rat model of mammary carcinogenesis. Female August Copenhagen Irish (ACI) rats were treated with vit C in the presence or absence of 17β-estradiol (E2) for 8 months. We demonstrate an increased expression of the miR-93 in E2-treated mammary tissues and in human breast cell lines and vit C treatment reverted E2-mediated increase in miR-93 levels. MiRNA target prediction programs suggest one of the target genes of miR-93 to be nuclear factor erythroid 2-related factor 2 (NRF2). In contrast with miR-93 expression, NRF2 protein expression was significantly decreased in E2-treated mammary tissues, mammary tumors, and in breast cancer cell lines, and its expression was significantly increased after vit C treatment. Ectopic expression of miR-93 decreased protein expression of NRF2 and NRF2-regulated genes. Furthermore, miR-93 decreased apoptosis, increased colony formation, mammosphere formation, cell migration and DNA damage in breast epithelial cells, whereas silencing of miR-93 in these cells inhibited these carcinogenic processes. Taken together, our findings suggest an oncogenic potential of miR-93 during E2-induced breast carcinogenesis.
authors.affiliation: Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Singh
authors.forename: Amruta M
authors.initials: AM
authors.lastname: Ronghe
authors.forename: Anwesha
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Nimee K
authors.initials: NK
authors.lastname: Bhat
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001205:Ascorbic Acid / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000009:adverse effects; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004967:Estrogens; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D004958:Estradiol; D001205:Ascorbic Acid