Abstract A52: The microRNA control of 17β-hydroxysteroid dehydrogenase type 1 and 2 in breast cancer

• Published in: Molecular cancer research 2016-02, Vol.14 (2_Supplement), p.A52-A52
• Main Authors: Hilborn, Erik, Stal, Olle, Jansson, Agneta
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1557-3125.ADVBC15-A52

Introduction: Breast cancer is primarily a steroid hormone dependent disease, and up to 80% of all breast cancers express the estrogen receptors. Regulation of steroid hormone activity in the breast tissue is mediated by the aromatase enzyme and by the 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme family. 17β-HSD1s primary role is in catalyzing the NADH dependent reduction of esterone to estradiol. 17β-HSD2 acts in opposition to 17β-HSD1 and mediates a NAD(H) dependent conversion of estradiol to esterone. The combination of these two enzymes has been shown to be a good indicator of tamoxifen treatment benefit, as tumors with a high 17βHSD1/17βHSD2 ratio have less benefit from tamoxifen treatment. Furthermore, patients with high 17βHSD1 mRNA expression were shown to have shorter overall disease free survival and increased risk of relapse. Despite this, next to nothing is known about the control of the expression 17βHSD1 and 17βHSD2 by microRNA in breast cancer. Aim: To identify key microRNA responsible for the regulation of 17βHSD1 and 17βHSD2 in breast cancer. Materials and methods: We screened for the effect of microRNA mimics by in vitro transient transfection of breast cancer epithelial cell-lines T47D, MCF-7 and ZR75-1 as well as the epithelial cell-line MCF10A. Results: The endogenous expression of 17β-HSD type 1 in MCF-7 is low while ZR75-1 and MCF10A express moderate levels and T47D expresses high levels. Here we show that microRNA-210, 4508, 1304-3p, 6832-5p, 892a and 3674 down regulate 17β-HSD type 1 mRNA levels to 20-60% of control levels in MCF-7 and T47D. The same miRs had either a reduced effect, or no effect in ZR75-1 and MCF10A. Furthermore, we show that miR-17, 873-5p, 744-5p and 4794 result in a 2-5 fold increase in the expression of 17β-HSD type 1 ZR75-1, T47D and MCF7. This effect was reduced to 0.5 fold in MCF10A. The endogenous expression of 17β-HSD type 2 is low in MCF7, moderate in ZR75-1 and T47D and very high in MCF10A. We show that miRs 2045p, 211-5p, 5006-3p, 4251, 4745-5p, 302d-5p, 498, 1305 and 205-3p down regulates 17β-HSD type 2 expression to 10-60% of endogenous levels in ZR75-1 and MCF7, and to 30-70% of endogenous levels in MCF10A. Conclusion: These findings are the first which start to map out the microRNA regulation of 17β-HSD type 1 and 2 in breast cancer, and this may be one important mechanism by which their expression levels are regulated in the pathogenesis of breast cancer. Citation Format: Erik Hilborn, Olle S