MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis

• Published in: Carcinogenesis (New York) 2013-05, Vol.34 (5), p.1165-1172
• Main Authors: Singh, Bhupendra, Ronghe, Amruta M, Chatterjee, Anwesha, Bhat, Nimee K, Bhat, Hari K
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Ascorbic Acid - pharmacology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; DNA Damage; Estradiol - pharmacology; Estrogens - adverse effects; Female; Humans; MicroRNAs - genetics; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Original Manuscript; Rats; Rats, Inbred ACI; Rats, Sprague-Dawley; Up-Regulation - drug effects
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt026

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.