miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets

Abstract

MicroRNAs (miRNAs) are short (22 nucleotides), single-stranded, non-coding RNAs that form complimentary base-pairs with the 3’ untranslated region of target mRNAs within the RNA-induced silencing complex (RISC) and block translation and/or stimulate mRNA transcript degradation. The non-coding miRBase (release 21, June 2014) reports that human genome contains ~2,588 mature miRNAs which regulate ~ 60% of human protein-coding mRNAs. Dysregulation of miRNA expression has been implicated in estrogen-related diseases including breast and endometrial cancers. The mechanism for estrogen regulation of miRNA expression and the role of estrogen-regulated miRNAs in normal homeostasis, reproduction, lactation, and in cancer is an area of great research and clinical interest. Estrogens regulate miRNAs transcription through estrogen receptors α and β in a tissue-specific and cell-dependent manner. This review focuses primary on the regulation of miRNA expression by ligand-activated ERs and their bona fide gene targets and includes miRNAs regulation by tamoxifen and endocrine disrupting chemicals (EDCs) in breast cancer and cell lines.

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

“…Progestins, estrogens, and androgens all regulate miRNAs [114–117], several of which have been linked to CSC formation in breast cancer cells (Fig. 1).…”

“…ER-regulated miRNAs in breast cancer cells have been reported by multiple laboratories [114]. While there are no specific studies on ER miRNAs and breast CSCs, ER upregulates several miRNAs involved in maintenance of differentiation including the let-7 miRNA family, proposed to repress self-renewal and promote differentiation in normal and cancer cells [120].…”

Human Adrenal Cortex: Epigenetics and Postnatal Functional Zonation

“…However, the contribution of DNA methylation to ERβ zone-specific expression in the human adrenal cortex has not been analyzed. Furthermore, estrogens regulate miRNA transcription through ERα and β in a tissue-specific and cell-dependent manner [58]. To consider a role for miRNAs in adrenal functional zonation, more information regarding the regulation of their own transcription is required.…”

Roles for miRNAs in endocrine resistance in breast cancer

“…Some of these miRNAs are regulated by E 2 and/or influence expression of estrogen-responsive genes (Ferraro, et al 2012; Klinge 2012, 2015). miRNAs have been implicated in regulating hallmarks of breast cancer (reviewed in (Goh, et al 2015)) including cell proliferation, cell death, apoptosis, immune response, cell cycle energetics, metabolism, replicative immortality, including senescence, invasion, and metastasis (reviewed in (McGuire, et al 2015; Negrini and Calin 2008; O’Day and Lal 2010; Singh and Mo 2013), and angiogenesis (reviewed in (Cortes-Sempere and Ibanez de Caceres 2011; Goh et al 2015)).…”