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Epigenetic and Expression Profiling of Tissue Selective Estrogen Compounds in Breast Epithelial Cell Lines (RNA-seq)

ABSTRACT: Current approaches to menopausal hormone therapy consist of compounds which provide tissue specific beneficial effects while working to minimize any increase in cancer risk associated with replacement therapy. In this study, an examination of the genomic distribution of histone modification and expression changes in two breast epithelial cell lines, the normal MCF10A cell line and the MCF-7 breast cancer cell line, upon treatment with several of the current therapies used for treating post-menopausal symptoms is presented. Analysis of the observed changes upon treatment with either 17-estradiol (E2), a combined treatment with the top 10 most abundant Premarin chemical equivalents (EC10), the non-steroidal SERM, Bazadoxifene (BZA) and the TSEC; BZA combined with EC10 (Duavee) or BZA combined with E2 provides evidence of expression changes in genes involved in DNA replication, nucleosome assembly, RNA-splicing and processing, biological regulation and cell signaling, and many of the known steroid response genes. There were distinct global changes in chromatin states observed that were specific to each of the breast epithelial cell type normal, basal MCF10A and ESR/PGR positive luminal breast cancer MCF7 cell lines and selective changes observed upon treatment with each of the treatment groups. Specifically, we observed a global loss of H3K4ac upon treatment with BZA. These changes were observed in both ESR1 bound and non-bound regions suggesting modifications in both promoters and enhancer regions. The levels of H3K4ac upon treatment of BZA showed a decrease below basal non-treated H3K4ac levels in MCF7. There was an increase observed with E2 and EC10 treatment in MCF7 that was mitigated by the addition of BZA to either steroid as a combined treatment. This study provides a better understanding of the role of epigenetic modifications in endocrine responsiveness and provides evidence of an improved therapeutic profile for combined TSEC compounds for treating and managing the overall physiological effects of declining estrogen.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102469 | GEO | 2020/08/01

REPOSITORIES: GEO

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Project description:Current approaches to menopausal hormone therapy consist of compounds which provide tissue specific beneficial effects while working to minimize any increase in cancer risk associated with replacement therapy. In this study, an examination of the genomic distribution of histone modification and expression changes in two breast epithelial cell lines, the normal MCF10A cell line and the MCF-7 breast cancer cell line, upon treatment with several of the current therapies used for treating post-menopausal symptoms is presented. Analysis of the observed changes upon treatment with either 17-estradiol (E2), a combined treatment with the top 10 most abundant Premarin chemical equivalents (EC10), the non-steroidal SERM, Bazadoxifene (BZA) and the TSEC; BZA combined with EC10 (Duavee) or BZA combined with E2 provides evidence of expression changes in genes involved in DNA replication, nucleosome assembly, RNA-splicing and processing, biological regulation and cell signaling, and many of the known steroid response genes. There were distinct global changes in chromatin states observed that were specific to each of the breast epithelial cell type normal, basal MCF10A and ESR/PGR positive luminal breast cancer MCF7 cell lines and selective changes observed upon treatment with each of the treatment groups. Specifically, we observed a global loss of H3K4ac upon treatment with BZA. These changes were observed in both ESR1 bound and non-bound regions suggesting modifications in both promoters and enhancer regions. The levels of H3K4ac upon treatment of BZA showed a decrease below basal non-treated H3K4ac levels in MCF7. There was an increase observed with E2 and EC10 treatment in MCF7 that was mitigated by the addition of BZA to either steroid as a combined treatment. This study provides a better understanding of the role of epigenetic modifications in endocrine responsiveness and provides evidence of an improved therapeutic profile for combined TSEC compounds for treating and managing the overall physiological effects of declining estrogen.

Project description:Altered expression of microRNAs (miRNAs), an abundant class of small non-protein-coding RNAs that mostly function as negative regulators of protein-coding gene expression, is common in cancer. Here we analyze the regulation of miRNA expression in response to estrogen, a steroid hormone that is involved in the development and progression of breast carcinomas and that is acting via the estrogen receptors (ER) transcription factors. We set out to thoroughly describe miRNA expression, by using miRNA microarrays and real time RTPCR experiments, in various breast tumor cell lines in which estrogen signaling has been induced by 17β-estradiol (E2). We show that the expression of a broad set of miRNAs decreases following E2 treatment in an ER-dependent manner. We further show that enforced expression of several of the repressed miRNAs reduces E2-dependent cell growth, thus linking expression of specific miRNAs with estrogen-dependent cellular response. In addition, a transcriptome analysis revealed that the E2-repressed miR-26a and miR-181a regulate many genes associated with cell growth and proliferation, including the progesterone receptor gene, a key actor in estrogen signaling. Strikingly, miRNA expression is also regulated in breast cancers of women who had received antiestrogen neoadjuvant therapy thereby showing an estrogen-dependent in vivo regulation of miRNA expression. Overall, our data indicates that the extensive alterations in miRNA regulation upon estrogen signalling pathway plays a key role in estrogen-dependent functions and highlights the utility of considering miRNA expression in the understanding of antiestrogen resistance of breast cancer. 9 samples analyzed. Triplicates were done. MCF-7+miR26a+E2 (n=1 to 3) ; MCF7+miRctrl+E2 (n=1 to 3) ; MCF7+miRctrl+vehicle (n=1 to 3). We generated pairwise comparisons using EASANA from GenoSplice technology: MCF-7+miR26a+E2 versus MCF7+miRctrl+E2 and MCF-7+miRctrl+E2 versus MCF7+miRctrl+vehicle. Fold change ≥1.5 were selected.

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Epigenetic and Expression Profiling of Tissue Selective Estrogen Compounds in Breast Epithelial Cell Lines (RNA-seq)

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