SAT-LB130 Tamoxifen Affects MiRNA Expression in Uterus and Breast Tamoxifen Affects MiRNA Expression in Uterus and Breast Tamoxifen Affects MiRNA Expression in Uterus and Breast

摘要

In addition to genetic factors, environmental factors and lifestyle can play a significant role in the development of hormone-dependent tumors, such as endometrial cancer (EC) and breast cancer (BC). The discovery of microRNAs (miRs) involved in the post-transcriptional regulation of many genes, including those of hormonal carcinogenesis, namely, steroid receptors and their target genes, strengthened the epigenetic direction in the study of carcinogenesis mechanisms. A critical event in the development of hormone-dependent human tumors is violation in the metabolism of steroid hormones, primarily estradiol. An interesting aspect of the problem of ERα inhibition is the use of tamoxifen (TAM) in clinical practice in the treatment of hormone-dependent BC. A well-known side effect of TAM is increased proliferation in the endometrium and an elevated risk of EC. One of the mechanisms explaining such differences in the effects of TAM is formation of DNA adducts in endometrial cells, but this mechanism has not yet been substantiated. Therefore, the problem of carcinogenesis of the uterus with this drug remains unresolved and requires further research. The aim of our study was to evaluate the expression of miRs and target genes for hormonal carcinogenesis in the uterus and mammary gland under the exposure with TAM. As an object of study, we used female rats, primary human cell cultures and tissues of TAM-induced human endometrial hyperplasia. The results showed that estradiol enhances the expression of oncogenic microRNAs miR-21-, 221, -222 by three-ten times, both in the rat mammary gland and endometrium, which confirms its oncogenic properties. In the rat endometrium, TAM, to a greater extent than estradiol, increased the expression of oncogenic miRs, especially miR-419, -23a, 24-2,- 27, and significantly reduced the expression of their target genes. In addition, TAM caused a multiple (8-fold) increase in the expression of cyclin D in uterus compared with mammary gland. In most cases, TAM reduced expression of oncogenic miR-21,-221,-222 by 50% in BC primary cell culture whereas in EC primary cell culture expression of oncogenic 190a was increased. We also investigated the activity of estrogen-metabolizing enzymes in tamoxifen-induced human endometrial hyperplasia. A significant difference was found in the expression of estrogen-metabolizing genes (CYP1A,1B, CYP19, SULT1A1, SULT1E1, GSTP1,2, COMT, STS) in TAM-induced endometrial hyperplasia, which may be due to the difference in miRNA expression. Thus, both for the animal model and human cell cultures, it was shown that TAM causes other changes in the expression of microRNAs in the endometrium compared with the breast. Further studies with the identification of target miRNA genes will help identify molecular targets of TAM-induced endometrial hyperplasia. This work was supported by Russian Science Foundation, grant # 19-15-00319.