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Review
. 2015 Dec 15;418 Pt 3(0 3):273-97.
doi: 10.1016/j.mce.2015.01.035. Epub 2015 Feb 3.

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

Carolyn M Klinge  1
Affiliations
Review

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

Carolyn M Klinge. Mol Cell Endocrinol. .

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 ∼ 2588 mature miRNAs which regulate ∼ 60% of human protein-coding mRNAs. Dysregulation of miRNA expression has been implicated in estrogen-related diseases including breast cancer and endometrial cancer. 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 miRNA transcription through estrogen receptors α and β in a tissue-specific and cell-dependent manner. This review focuses primarily on the regulation of miRNA expression by ligand-activated ERs and their bona fide gene targets and includes miRNA regulation by tamoxifen and endocrine disrupting chemicals (EDCs) in breast cancer and cell lines.

Keywords: Dicer; Drosha; Endocrine disrupting chemical; Endocrine-resistance; Estrogen; Estrogen receptor; Tamoxifen; Transcription; mRNA stability; miRNA.

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Conflict of interest statement

Conflict of interest: none

Figures

Figure 1
Figure 1. History of PubMed citations on human miRNA, estrogen AND miRNA, and tamoxifen AND miRNA
The search terms used were human AND miRNA (black closed circles) and human AND miRNA AND estrogen. Each point is the number of publications in the calendar year indicated. The number of citations was taken directly from an advanced search of PubMed and was not hand-curated to remove non-relevant citations.
Figure 2
Figure 2. Model of canonical miRNA biogenesis and function
Primary transcripts of microRNAs (pri-miRNAs) are transcribed by RNA polymerase II, processed by the RNAse III enzyme, Drosha and its cofactor DGCR8, to precursor microRNAs (pre-miRNAs) which are exported from the nucleus by Exportin/RAN-GTP (85). In the cytoplasm, pre-miRNAs are processed by the Microprocessor complex that includes Dicer, an RNAse III enzyme, to form mature ~22 nt transiently double-stranded miRNA duplexes that are transferred to Argonaute proteins (most notably AGO2 in the RNA-induced silencing complex (RISC), leading to unwinding of the duplexes to form single stranded miRNAs. The RISC complex binds either to the 3’ untranslated region (3’ UTR) or to the open reading frame (ORF) of its target mRNA. Binding of miRNA/RISC complex with the 3’UTR causes translational repression (18).
Figure 3
Figure 3. Overview of miRNAs regulating ERα and ERβ expression and function
MiRNAs that inhibit ERα, ERβ, and coregulators involved in gene transcription are indicated as discussed in the text.
See this image and copyright information in PMC

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