Review
miRNAs and estrogen action

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MicroRNAs (miRNAs) are short, noncoding RNAs that generally base-pair within the 3′ untranslated region of target mRNAs causing translational inhibition and/or mRNA degradation. Estradiol (E2) and other estrogen receptor (ER) ligands suppress or stimulate miRNA expression in human breast cancer cells, endometrial cells, rat mammary gland, and mouse uterus, and post-translationally regulate protein expression. Aberrant miRNA expression is implicated in estrogen-related breast and endometrial cancers, and several miRNAs downregulate ERα. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in health and disease is a ‘hot’ area of research that will yield new insight into molecular mechanisms of estrogen action.

Section snippets

miRNA biogenesis and regulation

The function of 80–93% of the expressed, non-protein-encoding ‘dark matter RNAs’ (excluding rRNA, mRNA, tRNA, and mtRNA) in the human is not yet fully understood [1]. The importance of noncoding RNAs (ncRNAs), which includes short interfering RNAs (siRNAs), microRNAs (miRNAs), and PIWI-interacting RNA (piRNAs), was recently reviewed [2].

miRNA are small (approx. 20–22 nt) ncRNAs that regulate mRNA translation or stability [3]. About half of miRNAs are intragenic, and most are found in the 5′

ERα, not ERβ, interacts with Drosha

ERα interacts with and suppresses Drosha activity in mouse uterine epithelial cells and MCF-7 cells [23] (Figure 1). ERα–Drosha interaction is enhanced by E2 and by ERα interaction with the p68 and p72 RNA helicases in the Drosha complex [23] (Figure 1). p68 and p72 coactivate ERα and increase its transcriptional activity, by interacting with the N terminus of ERα, but not ERβ [45]. The N terminus of ERα also interacts directly with an LXXLL motif in the C terminus of Drosha [23]. Liganded ERα

E2 and miRNA regulation of Dicer and Ago2

The expression and/or activity of Dicer is regulated by the MAPK pathway: phosphorylation of TRBP enhances the production of growth-promoting miRNAs, for example miR-17 and miR-20a, and inhibits let-7 tumor suppressor expression, at least in HeLa cells [48]. E2 rapidly activates the membrane-associated ERαs activities including activating MAPK in a variety of cell lines [49]; however, no one has evaluated the impact of membrane-initiated ERα regulation of Dicer activity. This possibility is

miRNA regulation of ERα

Although several programs predict miRNA target–gene interaction, such as TargetScan [52] and myMIR [53], specific miRNA–mRNA interaction must be confirmed experimentally by cloning the 3′-UTR of the target mRNA 3′ to a luciferase reporter, and then examining if the miRNA of interest reduces luciferase activity, in transiently transfected cells. Ten miRNAs have been identified as bona fide ERα regulators (reviewed in [13], unless cited here): miR-22 [54], miR-206; miR-221, 222; miR-18a, miR-18b,

Altered miRNA expression in breast cancer

Over 400 studies have been published identifying and examining miRNA in breast cancer with most studies using microarray with confirmation of selected changes by real-time PCR. Aberrant patterns of miRNA expression in human breast cancer have been reviewed (e.g. [65]). miRNAs whose expression is increased in tumor cells, often as a result of chromosomal or molecular genomic aberrations, and which inhibit the translational expression of tumor suppressor genes, are called oncomiRNAs or oncomiRs.

Is E2 synthesis and metabolism regulated by miRNAs?

Estrogens (E2, estrone, and estriol) regulate development and homeostasis in a wide variety of tissues including the reproductive tract, bone, vasculature, brain, and breast. Although the sequence of events leading to breast tumor formation are not completely understood, lifetime exposure to estrogens is a major risk factor for breast cancer development [71]. Some studies indicated that E2 is carcinogenic in human breast epithelial cells, perhaps through genotoxic metabolites, such as 4-OH-E2

miRNAs regulating ER activity by repressing coregulator (coactivator/corepressor) expression

ERs regulate gene transcription by recruiting coregulators that modify chromatin structure in a ligand-, gene-, and cell-specific manner [76]. Although miRNAs would be expected to affect estrogen-regulated gene expression by altering coregulator levels, there are only two reports on coregulator regulation by miRNAs directly affecting ER activity. miR-17-5p was found to inhibit translation of the ER coactivator SRC-3/AIB1/NCOA3 [77]. Transfection of CHO-K1 cells with miR-17-5p and ERα inhibited E

Estrogen regulation of miRNA expression

Because of its role in breast cancer, much of what we know about estrogenic regulation of miRNA expression comes from studies of how E2 treatment of breast cancer cell lines affects mature miRNA expression. Although it is likely that estrogens regulate miRNAs by both genomic (transcriptional) and ‘nongenomic’ mechanisms of action, for example plasma membrane ERα or GPR30- associated signaling cascades, investigators are only beginning to examine these pathways. A PubMed search for estrogen and

Global genome binding studies to identify E2-regulated miRNAs

GRO-seq (global nuclear run-on and sequencing) was used to identify the position and orientation of all engaged RNA polymerases (RNA pol I, II, and III) across the genome of MCF-7 cells treated with 100 nM E2 for 10, 60, or 160 min [27]. This study reported that ERα enhancer transcripts were predominately upregulated by E2, whereas the intergenic transcripts [which would include miRNAs and long intergenic noncoding (linc) RNAs] were predominantly downregulated. The authors identified 322

E2 or fulvestrant-regulated miRNA and their bona fide targets

Table S1 lists E2 or fulvestrant (ER antagonist, ICI182780)-regulated mRNAs and their bona fide (experimentally proven) targets. The major caveat is that the relationship between E2 or fulvestrant regulation of the miRNA and the concordant effect of E2 or fulvestrant on the mRNA gene target has rarely been examined, thus providing direction for future research.

miRNAs related to endocrine resistance in breast cancer

Approximately 40% of breast cancer patients are initially responsive to tamoxifen and other endocrine therapies relapse [91]. The mechanisms for acquired endocrine resistance, despite continued ERα expression, are complex [91]. To date, the role of microRNAs in endocrine resistance has been examined by relatively few investigators. miRNA-221/222 are overexpressed in tamoxifen-, fulvestrant-, and tumor necrosis factor (TNF)-resistant MCF-7 cell line derivatives 20, 92, 93 and in ERα negative

Concluding remarks

E2 and 4-OHT stimulate and repress miRNA expression in a cell- and tissue-specific manner through ERα and, possibly, ERβ. Little is known about how other ER ligands affect miRNA expression or how miRNAs may affect the synthesis or metabolism of E2 and other estrogens. Because ERα interacts with components of the miRNA biogenesis pathway, more research is needed to distinguish E2 regulation at the level of pri-miRNA transcription versus miRNA processing and whether transcriptional or

Conflict of interest

None

Acknowledgments

Special thanks to Dr. Barbara J. Clark for her astute reading and comments to improve this review.

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