miRNAs and estrogen action

Abstract

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 (E(2)) 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.

Figure 1. The miRNA processing pathway

The figure illustrates the steps in the processing of miRNA, also summarized in the text. miRNAs are transcribed by RNA polymerase II into primary-miRNAs (pri-miRNAs) that are processed into precursor-miRNAs (pre-miRNAs) by the Drosha microprocessor complex which includes DGCR8. The DEAD-box RNA helicases p68 and p72 are components of the Drosha complex. Pre-miRNAs are recognized by exportin-5 and Ran-GTP with GTP hydrolysis allowing export to the cytoplasm. In the cytoplasm, pre-miRNAs are processed by the Dicer complex to mature ~22 nt miRNA. The TRBP/PACT complex interacts with and stabilizes Dicer, and transfers miRNA to Argonaute proteins (Ago1, Ago2, Ago3, and Ago4) in the RNA-induced silencing complex (RISC). miRNA guides the RISC complex to target mRNAs by binding to the 3′ UTR or the ORF and represses translation. The silenced mRNA is directed to the P-bodies for degradation. Interactions of ERα with Drosha, p68, and p77; regulation of Ago2 and Dicer; and possible regulation by nongenomic E₂ signaling (------) are indicated.

Figure 2. miRNA regulation of ERα and subsequent ERα transcriptional activity

ERα is downregulated by miR-18a,b; miR-193, miR-302c, miR-206, miR-22, miR-221, and miR-222. ERα forms a negative regulatory loop with miR-221,222, and 206 (red lines). Sp1 increases ERα expression (green arrow) and ERα interacts directly (double headed arrow) with Sp1 to regulate gene transcription. Whether ERα is a bona fide target of Let-7a, 7b, and 7i has not been experimentally verified (dotted line). ERα interacts with coregulators including SRC-1/NCOA1, SRC-3/AIB1/NCOA3, RIP140/NRIP, SMRT/NCOR2, and LCoR/LCOR which are downregulated by the miRNAs indicated. The regulation of miRNA gene transcription by ligand-occupied ERα is shown in Table 1 (Stimulation) and Table 2 (Suppression).