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Estrogen Regulation of MicroRNA Expression

Carolyn Klinge

Current Genomics · 2009

doi:10.2174/138920209788185289

Abstract

Women outlive men, but life expectancy is not influenced by hormone replacement (estrogen + progestin) therapy. Estrogens appear to protect brain, cardiovascular tissues, and bone from aging. Estrogens regulate genes directly through binding to estrogen receptors alpha and beta (ERalpha and ERbeta) that are ligand-activated transcription factors and indirectly by activating plasma membrane-associated ER which, in turns, activates intracellular signaling cascades leading to altered gene expression. MicroRNAs (miRNAs) are short (19-25 nucleotides), naturally-occurring, non-coding RNA molecules that base-pair with the 3' untranslated region of target mRNAs. This interaction either blocks translation of the mRNA or targets the mRNA transcript to be degraded. The human genome contains ~ 700-1,200 miRNAs. Aberrant patterns of miRNA expression are implicated in human diseases including breast cancer. Recent studies have identified miRNAs regulated by estrogens in human breast cancer cells, human endometrial stromal and myometrial smooth muscle cells, rat mammary gland, and mouse uterus. The decline of estradiol levels in postmenopausal women has been implicated in various age-associated disorders. The role of estrogen-regulated miRNA expression, the target genes of these miRNAs, and the role of miRNAs in aging has yet to be explored.

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Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Women live longer than men. Estrogens (estradiol, estrone, and estriol) are steroid hormones that regulate development and homeostasis in a wide variety of tissues including the brain, reproductive tract, vasculature, and breast. Estradiol (E2) is synthesized in the ovary and is the primary estrogen in premenopausal women. Animal studies have shown that higher estrogen levels in females protect against aging by upregulating the expression of antioxidant, longevity-related genes, e.g., selenium-dependent glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD), by protecting against stroke-related injury, by vasorelaxing effects, by direct myocardial protection, and by activating the insulin receptor substrate (IRS)-1 signaling pathway. Women’s life expectancy seems not to be influenced by hormone replacement therapy (HRT = estrogens plus a progestin, usually conjugated equine estrogens and medoxyprogesterone acetate (MPA)) in postmenopausal women, but atherosclerosis and bone loss are considerably delayed. In addition, HRT protects against Alzheimer’s disease (AD), perhaps by suppressing elevated gonadotropin levels, i.e., luteinizing hormone (LH), in postmenopausal women since elevated LH is thought to play a key role in AD pathogenesis. Other age-associated impairments are also reduced by estrogen. For example, premenopausal women have a reduced risk for cataracts compared with men of the same age group and women in the Farmingham study who used estrogen replacement therapy (ERT) showed reduced risk for cataracts. miRNAs are a class of naturally-occurring, small, non-coding RNA molecules that are related to, but distinct from, small interfering RNAs (siRNAs) which regulate mRNA translation or stability. There are very few studies on the hormonal regulation of miRNAs expression. Select changes in microRNA (miRNA) expression correlate with diagnostic markers used in breast cancer therapies, e.g., estrogen receptor α (ERα) and tumor grade. However, there are only 5 reports that E2 regulates miRNA expression that will be reviewed here. It is highly likely that hormones play a major role in regulating miRNAs by both genomic (transcriptional) and non-genomic mechanisms of action. Identification and characterization of estrogen-regulated miRNAs may provide new biomarkers and therapeutic targets in aging as well as in diseases including breast cancer.

Genomic ER Activities

Initiation of transcription is a complex event occurring through the cooperative interaction of multiple factors at the target gene promoter. I will use the term ER to refer to either ERα or ERβ or to both subtypes. I will refer to each subtype individually as pertinent to the known functions of these two proteins. Estrogen action is primarily mediated through binding to ER. ERα and ERβ are members of the steroid/nuclear receptor superfamily of proteins of which there are 48 members in mammals. ERα and ERβ are highly conserved within the DNA binding domain (DBD, C domain), but differ in their N- and C- termini. Structurally, ER has 6 domains lettered A-F from N- to C-terminus. ER is believed to be the ancestral steroid receptor originating 600-1200 million years ago, presumably because of the role of estrogens in reproduction and maturation.

In the simplest model, the binding of estradiol (E2) via hydrogen bonding to residues within the ligand binding pocket of the ligand binding domain (LBD, E domain) results in conformational changes termed activation. These conformational changes induced by E2 binding result in loosening of contact between the N-terminus and the C-terminus of ERα and exposes nuclear localization signals within the DNA binding domain (DBD, C domain) and hinge region (D domain) as well as altering structure of the LBD. Crystal structure studies of the LBD of ERα excluding the F domain shows that the LBD has 12 alpha helices and E2 binding repositions helix 12 such that activation function-2 (AF-2) is exposed. Helix 12 acts as a “switch” controlling accessibility of the coregulator interaction site. Ligand binding also facilitates ER dimerization (homodimerization or heterodimerization of ERα and ERβ).

E2-liganded ER interacts directly with a specific DNA sequence called the estrogen response element (ERE = 5’-AGGTCAnnnTGACCT-3’), historically located in the promoter region and currently established to be located at great distances from the transcription start site including in the 3’ flanking regions of target genes. DNA binding increases ER interaction with basal transcription factors and coregulator proteins (reviewed in). Fig. (1) depicts essential features of genomic ER action. EREs are enriched in genes upregulated by E2-ERα, at least in MCF-7 cells. ERα can also be activated by phosphorylation of ser118 in the N-terminal A/B domain that activates activation function-1 (AF-1) in the absence of ligand binding. At least in HeLa cells transfected with fluorescent fluorescent-tagged ERα (GFP- or CFP- ERα), E2 causes rapid intracellular and intranuclear movement of ERα to form punctuate nuclear speckles that appear to indicate ERα-nuclear matrix interaction. In addition to direct ER-ERE binding, ER also activates transcription via a “tethering mechanism” in which ER interacts directly with transcription factors, e.g. Sp1 and AP-1, bound to their response elements. These DNA-protein and protein-protein interactions recruit coactivator/chromatin remodeling complexes resulting in histone modifications that lead to nucleosomal remodeling, increased accessibility to the DNA template for RNA polymerase II interaction, and increased target gene transcription (reviewed in).

By definition, coactivators are proteins that interact directly with transcription factors to enhance transcription. It is important to note that the term coactivator or corepressor is used when referring to an ER (or other NR) coregulator is gene-, cell-type, and context- specific. This indicates that proteins classified as coactivators can also repress transcription and corepressors such as SMRT are gene- and cell- specific coactivators for ER. Coactivators promote the assembly of the transcription initiation complex in part by altering chromatin structure and ‘loosening’ DNA-histone interactions, facilitated by increased histone lysine residue acetylation, methylation, ubiquitination, or sumoylation. Once the transcription initiation complex is complete, RNA polymerase II (RNA pol II) is recruited to the transcription start site and begins transcription. By my count, at least 60 different ER coactivators and 23 corepressors have been functionally identified (reviewed in, see also http://www.nursa.org/index.cfm). The current model predicts that ERE-bound, agonist-liganded ER recruits coactivator proteins to enhance gene expression. In contrast for those genes at which tamoxifen (TAM) is an antagonist of ER transactivation, the LBD of TAM- occupied ERα does not interact with coactivators due to key conformational differences between agonist and antagonist – occupied ERα in AF-2. TAM-occupied ERα interacts with corepressors, e.g. NCoR or SMRT, that recruit histone deacetylase (HDAC) complexes thus keeping chromatin condensed and blocking transcriptional activation. Antiestrogen ICI 182,780 (Fulvestrant)-occupied ERα is targeted to the 26S proteasome for degradation. In contrast, although ICI 182,780 inhibits ERβ-mediated transcription, it stabilizes the ERβ protein.

Nongenomic Estrogen Action

In addition to its classical genomic/transcriptional effects mediated by ER-DNA interaction, described above, E2 has rapid “nongenomic, extra-nuclear, or membrane-initiated” effects that occur very rapidly, i.e., within seconds-minutes after E2 administration. These effects are independent and distinct from the genomic, i.e., ER-mediated transcription, activities reviewed in the preceding section. Fig. (1) highlights some of the established nongenomic activities of ER. Rapid estrogen-stimulated intracellular activities are mediated by plasma membrane (PM)-associated ER and/or by an ‘orphan’ G-protein coupled receptor GPR30. Evidence of a PM-associated ER population is supported by experiments in which a cell-impermeable E2–bovine serum albumin or other E2-conjugate was shown to rapidly initiate intracellular kinase cascade activities including MAPK/ERK (p42/p44 MAPKs), endothelial nitric oxide synthase (eNOS), and PI3K/AKT. In MCF-7 cells, E2 rapidly increased PIP2-phospholipase C activity, mobilized intracellular Ca2+, activated MAPK, and PI3K/AKT. Immunohistochemical techniques have visualized membrane ERα in a variety of cell types including endometrial and breast cancer cells, pituitary cells, and lung cancer cells/tumors. ERβ was shown to be located in the PM of primary cortical neurons in recent confocal imaging studies. Overall, the PM localization of ER appears to be cell type-specific.

Premenopausal women have a lower risk of developing cardiovascular disease and hypertension than men or post-menopausal women and estrogens are thought to be responsible for regulating peripheral resistance as well as effects in the myocardium. Many of the cardioprotective activities of E2 may be mediated by nongenomic signaling. Cumulative studies show that a subpopulation of intact ERα is associated with the endothelial PM and with caveolae. Recent electron microscopy studies revealed nuclear, cytoplasmic, and plasma membrane localization of both ERα and ERβ in human umbilical vein endothelial cells (HUVEC). ERα has been shown to interact with caveolin-1 (Cav-1) which serves as a structural core for interaction of plasma-membrane-associated proteins including the α-subunit of G-proteins, Ha-Ras, Src-kinases, eNOS, epidermal growth factor (EGF) receptors, and some protein kinase-C isoenzymes. E2-ERα interaction within caveolae leads to Gαi activation, MAPK and Akt signaling, and perturbation of the local Ca+2 environment, leading to eNOS phosphorylation and NO production. Endothelial PM-associated ERα is coupled via a Gαi to MAPK and eNOS.

The mechanism by which ERα and its splice variant ERα46 localizes to the PM involves palmitoylation. In addition, ER interaction with intracellular proteins is important in PM association. In MCF-7 cells, the adaptor proteins Shc shuttles ERα from the nucleus to the PM where ERα interacts with the IGF-1 receptor (IGF-1R). Similarly, another scaffold protein, called MNAR (modulator of nongenomic activity of ER), has been implicated in ERα-cSrc interaction and MAPK signaling. A role for a membrane caveolae-localized ERα46 in rapid NO release via PI3K/Akt activated eNOS has been reported in endothelial cells.

In addition to PM-associated ER, GPR30 has reported to serve as a membrane estrogen receptor because it binds E2 with high affinity (Kd = 2.7nM) and activates adenylate cyclase, thus increasing cAMP levels. GPR30 is distinct from ERα and ERβ in that ICI 182,780 and tamoxifen also bind GPR30 with high affinity and mimic the effects of E2. Although the role of GPR30 in MCF-7 and SKBr3 breast cancer cells has been questioned, it appears likely that GPR30 is a bone fide membrane estrogen receptor in some cell types.

MicroRNAs (miRNAs)

Evidence from the Encyclopedia of DNA project (ENCODE) has revealed surprising new information about the human genome. For example, although the protein coding regions account for only 2% of the total DNA in the human genome, surprisingly, 80-93 % of the genome is “expressed”. The transcribed RNAs are largely conserved between humans and mice suggesting that these noncoding RNAs (ncRNAs) have important functions. Evidence of the importance of the various types of ncRNAs was recently reviewed and includes roles in cancer, diabetes, and coronary disease, all aging-associated disorders. Among the small ncRNAs are microRNAs (miRNAs). The importance of miRNAs is highlighted by the fact that the 2008 Albert Lasker Award for Basic Medical research was awarded to Drs. Victor Ambros and Gary Ruvkun who discovered and characterized the first miRNAs in C. elgans and Dr. David Baulcombe who discovered let-7 miRNA in plants (see also http://www.laskerfoundation.org/).

miRNAs are a class of naturally-occurring, small, non-coding RNA molecules that are related to, but distinct from, small interfering RNAs (siRNAs). About half of miRNAs are expressed from introns of protein-coding transcripts and miRNAs have 5' and 3' sequence features that form boundaries including transcription start sites, CpG islands, and transcription factor binding recognition elements. miRNAs may be differentially processed from the sense and antisense strands of the same hairpin RNA or transcripts from the same locus, thus expanding the number of miRNAs from a single genomic locus.

The pathway of mature miRNA biogenesis is depicted in Fig. (2). miRNA genes are mostly transcribed by RNA polymerase II into primary-micro-RNAs (pri-miRNAs) that are capped and polyadenylated. Pri-microRNAs contain self-base-pairing stem-loop structure that is necessary for critical processing within the nucleus by Drosha, an endonuclease of the RNAse III family, and its cofactor DGCR8 into short (60 to 70 nt) imperfect hairpin structure precursor-miRNAs (pre-miRNAs). These pre-miRNAs are exported from the nucleus by exportin and Ran-GTP. Pre-miRNAs are processed by the cytoplasmic RNAse II enzyme Dicer to form mature ~22 nt transiently double-stranded miRNA duplexes that are transferred to Argonaute proteins (Ago1, Ago2, Ago3, and Ago4) in the RNA-induced silencing complex (RISC), leading to unwinding of the duplexes to form single stranded microRNAs. RISC guides RNA silencing with the miRNA binding either to the 3’ untranslated region (3’ UTR) or to the open reading frame (ORF) of its target mRNA. Most commonly, because of imperfect complimentarity of the base pairing between the miRNA and the 3’UTR, the RISC complex causes translational repression by RISC interaction with eIF6 which prevents assembly of 80S ribosomal assembly or by inhibition of translation. Thus, miRNA-mRNA 3’UTR interaction results in a decrease in target protein, not mRNA. The 7 to 8 nucleotide region of basepairing between the 5’ end of the mature miRNA and the mRNA is called the ‘seed sequence’. Base pairing of the miRNA-RISC complex within the ORF requires almost perfect complimentarity for its mRNA target and the mRNA is either degraded or translation is blocked. The miRNA-containing ribonucleoprotein particle (miRNP)-silenced mRNA is directed to the P-bodies, where the mRNA is either released from its inhibition upon a cellular signal and/or actively degraded. Comparative genomics analyses have revealed that over 45,000 miRNA binding sites within human 3'UTRs that are conserved above background levels. This number was reported to indicate that more than 60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Recent evidence indicates that miRNAs may also increase translation of select mRNAs in a cell cycle-dependent manner.

miRNAs have been demonstrated to play important roles in regulating various cellular processes including replication, differentiation, and apoptosis. Since each of these processes play a role in aging, it is reasonable to suggest that altered expression and function of miRNAs regulate aging. The role of miRNAs in aging is completely unexplored. The human genome contains > 700-1,200 miRNAs http://microrna.sanger.ac.uk/sequences/ and miRNAs are expressed in a tissue-specific manner. Each miRNA targets ~ 200 transcripts directly or indirectly, but the bone fide physiological targets of the vast majority of miRNAs is virtually unknown.

Altered miRNA Expression in Breast Cancer

The spectrum of miRNAs expressed in solid tumors, i.e., prostate, colon, stomach, pancreas, lung, and breast, is different from normal tissues. Although the precise sequence of events leading to breast tumors is not understood, lifetime exposure to estrogens is widely accepted as a major risk factor for the development of breast cancer. Some investigators have documented that E2 is carcinogenic in human breast epithelial cells. However, epidemiological evidence disputing the carcinogenicity of E2 in humans has been published. Surprisingly, there are no published studies evaluating the effect of E2 on global miRNA expression in breast cancer cells.

Aberrant patterns of miRNA expression have been reported in human breast cancer and recently reviewed. The first miRNA study in breast cancer indicated differential expression of miRNAs in concordance with other well-established markers of breast cancer stage and patient prognosis including ERα and PR expression, tumor stage, number of positive lymph nodes, and vascular invasion. Different miRNA expression profiles were also associated with ErbB2+ versus ER+ tumors. More recently, patients whose breast tumors showed reduced miR-126, miR-206, or miR-335 were found to have reduced survival, regardless of ERα or ErbB2 status.

A number of genes involved in breast cancer progression have been identified by in silico analysis to be targets of miRNAs that are deregulated in breast cancer and some have been experimentally proven. A recent study reported that miR-21 expression was reduced in breast tumors and that antisense to miR-21 suppressed MCF-7 breast cancer cell growth in vitro and as tumor xenografts in mice by regulating Bcl-2. Interestingly, we recently reported that overexpression of miR-21 in MCF-7 cells increased soft agar colony formation, reflecting increased tumorigenicity of these cells. We demonstrated that miR-21 binds to a seed element in the 3'-UTR of the programmed cell death 4 (PDCD4) gene and reduces Pdcd4 protein expression.

The breast cancer oncogene/coactivator AIB1/SRC-3/NCOA3 is regulated by mir-17-5p and there is a reciprocal relationship between reduced miR-17-5p and increased AIB1 in breast cancer cells. Overexpression of miR-17-5p reduced E2-stimulated proliferation of MCF-7 breast cancer cells, indicating a role for deregulation of miR-17-5p in breast cancer. Overexpression of miR-125a and miR-125b decreased ERBB2 and ERBB3 mRNA and protein levels, inhibited phosphorylation of ERK1/2 and AKT, and inhibited the anchorage-independent growth of ERα-negative/ErbB2-overexpressing SKBR3 breast cancer cells. ERα mRNA stability is negatively regulated by miR-206 in MCF-7 cells and miR-206 expression is higher in ERα negative MDA-MB-231 cells.

Estrogenic Regulation of miRNA Expression

A PubMed search for estrogen AND miRNA revealed 27 papers. However, in that list and in total there are, to my knowledge, only 6 studies in which miRNA regulation by E2 has been directly examined (see below). Indeed, although a software application that will retrieve all miRNA:mRNA functional pairs in an experimentally derived set of genes was recently developed and used to identify E2-regulated mRNA genes in breast cancer, this paper does not experimentally address miRNA changes regulated by E2.

E2 Regulation of miRNAs in Animal Studies

The effect of E2 in miRNA expression has been examined in zebrafish, August Copenhagen Irish (ACI) rats, and mouse splenocytes. A recent review of miRNA expression in female mammalian reproductive tissues described transgenic and knockout mouse models and findings related to changes in miRNAs in the ovary and uterus in response to deletion of Dicer, LH, and during development (immature versus mature mice). Changes in miRNA expression in mouse uterus during implantation have been cataloged. Importantly, the authors of this review concluded that the expression, regulation, and function of miRNAs within specific tissues and cells still needs to be determined.

A study of the effect of E2 on miRNA expression in the adult (3 mos) zebrafish male (Danio rerio) identified altered expression of 38 miRNAs in the whole body homogenates. E2 was added to the aquariums at a final concentration of 5 µg/liter (18 nM) and although various times of treatment were analyzed, most miRNA changes in response to E2 were observed after 12 h. miRNAs were regulated by E2 in a tissue-specific manner with E2 downregulating miRNAs in the liver and increasing miRNA expression in the skin of the zebrafish. For example, miR-122 was decreased by E2 in skin, but increased in gills, intestine. and liver. Among the most up-regulated miRNAs were miR-196b and let-7h, and miR-130c and miR-101a were the most down-regulated. The authors identified Hoxb8a as a target of miR-196b and showed that E2, by increasing miR-196b, decreased Hoxb8a. The authors concluded that miR-196b may serve as “a biomarker of exposure to environmental estrogens and endocrine-disrupting chemicals that fish may encounter in their aquatic environment”.

In another study, miRNA expression was analyzed after 6, 12, and 18 weeks of E2-induced mammary carcinogenesis in female ACI rats. After 6 and 12 wks of E2 exposure, 15 miRNAs were down-regulated, e.g., miR-22, miR-99a, miR-106a, miR-127, miR-499, and 19 miRNAs were-up-regulated, e.g., miR-17-5p, miR-20a, miR-21, miR-129-3p, miR-106a, miR-22, and miR-127. By 18 wks of E2 treatment, the mammary glands were characterized by lobular involution and hyperplasia, and only 1 miRNA was down-regulated (miR-139) and 5 miRNAs were up-regulated (miR-20b, miR-21, miR-103, mir-107, miR-129-3p, and miR-148a). Genes targeted by three of the altered miRNAs were examined: miR-20a regulates E2F1, miR-106a regulates RBI, and miR-127 regulates BCL6. Western blot of mammary gland lysates after 12 wks of E2 showed that levels of RBI and E2F1 were decreased and BCL6 protein was increased, data that are in agreement with the increase miR-20a and miR-106a and the decrease in miR-127 detected.

E2 decreased miR-146a, miR 125a, miR-125b, let-7e, miR-126, miR-145, and miR-143 and increased miR-223, miR-451, miR-486, miR-148a, miR-18a, and miR-708 expression in mouse splenic lymphocytes. Notably, transfection of cells with miR-146a decreased LPS-induced IFNγ. AS to miR-223 blocked LPS-induced IFNγ secretion in splenocytes from E2 treated mice. This is the first report on E2 regulation of miRNA expression in immune cells, but provided no mechanism by which E2 regulated these changes.

E2 Regulation of miRNAs in Human Cell Lines

E2 and the ERα-selective agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) decreased miR-206 expression in MCF-7 cells whereas 2,3-bis(4-hydroxy-phenyl)propionitrile (DPN), an ERβ-selective agonist, increased miR-206, pointing to a regulatory loop. Interestingly, miR-206 also reduced β-actin. The authors of this report called miR-206 a “tumor suppressor” and found that miR-206 was higher in ERα-negative MDA-MB-231 cells, offering a mechanism, in addition to ERα promoter methylation, for reducing ERα expression in MDA-MB-231 cells.

A study identifying miRNAs expressed in myometrial and leiomyoma smooth muscle cells (MSMC and LSMC) using microarray and real time PCR reported that E2 inhibited the expression of miR-21 in MSMC and LSMC, whereas E2 increased and inhibited miR-26a in MSMC and LSMC, respectively. In contrast, ICI 182,780 increased the expression of miR-20a and miR-21 in MSMC and LSMC, and miR-26a in MSMC, while inhibiting the expression of miR-26a in LSMC. No mechanistic studies or mRNA target gene studies were performed to identify the mechanism(s) involved in these cell-specific differences in miRNA regulation by E2 and ICI or their downstream targets.

To identify E2 regulated miRNAs in a classical estrogen-responsive human breast cancer cell line, we treated ERα-positive MCF-7 cells with 10nM E2 or EtOH (vehicle control) for 6 h to identify primary E2 target miRNAs. RNA was harvested, labeled either with Cy3 or Cy5, and hybridized with two identical, dual-color miRNA microarrays from LC Sciences. This array contained probes to detect mature miRNA sequences as well as precursor (pre)-miRNAs in the Sanger miRNA registry 7.0 (http://microrna.sanger.ac.uk/ sequences/). The differentially expressed transcripts that were consistent on both chips are summarized in Table 1. 38 miRNA genes were regulated by E2: 9 were reduced and 29 were increased. A summary about what is known about each of these E2-responsive miRNAs in terms of breast cancer and estrogen-responsiveness is included in Table 1.

miRNAs Regulating ER Expression or Activity

miRNAs can influence estrogen-regulated gene expression by directly reducing ERα mRNA stability or translation. Four miRNAs have been reported to reduce ERα protein levels (Fig. 3). Two miR-206 recognition sites were identified in the 3’UTR of ERα and transfection of an expression vector for miR-206 in MCF-7 cells reduced both mRNA and protein levels of ERα. Treatment of MCF-7 cells with 1nM E2 or the ERα agonist PPT (10nM) reduced miR-206 levels by ~ 80%. In contrast the ERβ agonist DPN (10nM) increased miR-206 expression by ~ 60%. Interestingly, the investigators found that miR-206 levels were significantly higher in ERα-negative MDA-MB-231 cells than in MCF-7 cells, suggesting a mechanism for miR-206 in repressing ERα protein levels in MDA-MB-231 cells. The authors suggested that miR-206 may function in a mutually negative feedback loop to temporally regulate ERα expression and ductal/lobuloalveolar proliferation. More recent studies showed that miR-206 is inversely correlated with ERα expression, but not ERβ, in human breast tumors. Further, transfection of MCF-7 human breast cancer cells with an expression plasmid for pre-miR-206 reduced ERα mRNA expression ~ 25%, reduced the basal expression levels of PR, cyclin D1, and pS2 (all well-established ERα-regulated genes), and inhibited cell proliferation with or without E2.

miR-221/222 was recently reported to be higher in ERα negative than ERα positive breast cancer cell lines and human breast tumors. Two miR-221 and miR-222 seed elements were identified in the 3’UTR of ERα and transfection of miR-221 and miR-222 suppressed ERα protein, but not mRNA in ERα positive MCF-7 and T47D cells. Conversely, knockdown of miR-221 and miR-22 in ERα-negative MDA-MB-468 partially restored ERα protein expression and increased tamoxifen-induced apoptosis.

miR-22 regulates ERα protein expression in a pancreatic cancer cell line. In a study to identify curcumin gene targets, curcumin increased miR-22 by 65% in BxPC-3 human pancreatic carcinoma cells. One of the predicted 3’UTR gene targets of miR-22 was ESR1 (ERα). Follow-up studies showed that curcumin reduced ERα protein expression in BxPC-3 cells and that transfection of an antisense RNA oligonucleotide of miRNA-22 into BxPC-3 cells increased ERα protein by ~ 1.9-fold. Thus, miR-22 regulates ERα protein levels and the authors suggest a role for ERα as anti-tumorigenic in pancreatic cancer.

miRNAs can affect estrogen-regulated gene expression by reducing the expression of the coactivator SRC-3/AIB1/ NCOA3. miR-17-5p was demonstrated to inhibit translation of SRC-3/AIB1/NCOA3. Transfection of CHO-K1 cells with ERα and miR-17-5p inhibited E2-stimulated ERE-driven luciferase reporter activity by 50%. This report also demonstrated that transfection of MCF-7 cells (which do not express miR-17-5p) with miR-17-5p reduced E2-induced proliferation and E2-induced endogenous cyclin D1 transcription.

E2 Regulation of Ago2 and ERα in Human Breast Cancer Cell Lines

Argonaut-2 (Ago2), the catalytic subunit of the RISC complex that mediates miRNA-dependent cleavage/degradation in mammals, expression is higher in ERα-negative, HER2-positive (basal) than ERα-positive/HER2 negative (luminal) human breast cancer cell lines and tumors. E2 and the ERα-agonist PPT, but not the ERβ-agonist DPN, increased Ago2 protein expression in MCF-7 cells. Further studies showed that EGF acts through the MAPK pathway to increase Ago2 protein stability, but there were no studies examining the mechanism by which E2 and PPT, presumably through ERα, increase Ago2 protein levels. Surprisingly, Ago2 overexpression in MCF-7 cells increased ERα protein levels by 3-fold, despite also increasing miR-206 that reduces ERα. The authors concluded that this “discordant” finding indicates that there is a greater concentration of miRNAs than target proteins involved in ERα suppression than those that target ERα itself”.

CONCLUSION

Estrogen signaling plays a critical role in regulating reproduction, lactation, bone density, cardiovascular function, neuronal signaling, immune function, and homeostasis in a wide variety of tissues. The reduction in serum E2 in postmenopausal women is involved in a number of age-associated disorders. Research on the mechanisms by which E2 and other estrogens regulate diverse physiological effects has established both genomic and nongenomic mechanisms involving ERα, ERβ, and GPR30 in signal transduction (Fig. 1). miRNAs are small, non-coding RNAs that bind to the 3’ UTR of target mRNAs and either block the translation of the message or bind the ORF and target the mRNA transcript to be degraded. Although there are a number of studies identifying miRNA changes in breast tumors and comparing ERα-positive versus ERα-negative miRNA signatures for their potential use as biomarkers, there are few studies identifying E2-responsive miRNAs in any normal or neoplastic tissues or cell models. In those few studies that have identified E2-induced alterations in miRNA expression, there is little, if any, mechanistic detail elaborated for the E2 effect (s) on miRNA expression. Further, it appears that E2 regulates miRNA expression in a cell-type-dependent manner. Thus, identification of E2-regulated miRNAs and the function of miRNAs within specific tissues and cells still remains to be determined.

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    Not in our library10.1073/pnas.0803304105

  16. 16.

    Lowery AJ, Miller N, McNeill RE, Kerin MJ. MicroRNAs as prognostic indicators and therapeutic targets: potential effect on breast cancer management. Clin. Cancer Res. 2008;14:360-365.

    Not in our library10.1158/1078-0432.ccr-07-0992

  17. 17.

    Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, Jacob S, Majumder S. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27(kip1). J. Biol. Chem. 2008;283:29897-29903.

    Not in our library10.1074/jbc.m804612200

  18. 18.

    Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451:147-152.

    Not in our library10.1038/nature06487

  19. 19.

    Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M, Wu K, Whittle J, Ju X, Hyslop T, McCue P, Pestell RG. A cyclin d1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J. Cell Biol. 2008;182:509-517.

    Not in our library10.1083/jcb.200801079

  20. 20.

    Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065-7070.

    Not in our library10.1158/0008-5472.can-05-1783

  21. 21.

    Jiang J, Lee EJ, Gusev Y, Schmittgen TD. Real-time expression profiling of microRNA precursors in human cancer cell lines. Nucleic Acids Res. 2005;33:5394-5403.

    Not in our library10.1093/nar/gki863

  22. 22.
    Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. · 2006
    No notice
  23. 23.

    Maglich JM, Sluder A, Guan X, Shi Y, McKee DD, Carrick K, Kamdar K, Willson TM, Moore JT. Comparison of complete nuclear receptor sets from the human, caenorhabditis elegans and drosophila genomes. Genome Biol. 2001;2.

    Not in our library10.1186/gb-2001-2-8-research0029

  24. 24.

    Klinge CM. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 2001;29:2905-2919.

    Not in our library10.1093/nar/29.14.2905

  25. 25.

    Thornton JW. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc. Natl. Acad. Sci. USA. 2001;98:5671-5676.

    Not in our library10.1073/pnas.091553298

  26. 26.

    Thornton JW, Need E, Crews D. Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science. 2003;301:1714-1717.

    Not in our library10.1126/science.1086185

  27. 27.

    Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. Proc. Natl. Acad. Sci. USA. 1998;95:5998-6003.

    Not in our library10.1073/pnas.95.11.5998

  28. 28.

    Metivier R, Stark A, Flouriot G, Hubner MR, Brand H, Penot G, Manu D, Denger S, Reid G, Kos M, Russell RB, Kah O, Pakdel F, Gannon F. A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant a and e domains. Mol. Cell. 2002;10:1019-1032.

    Not in our library10.1016/s1097-2765(02)00746-3

  29. 29.

    Ruff M, Gangloff M, Wurtz JM, Moras D. Estrogen receptor transcription and transactivation: structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res. 2000;2:353-359.

    Not in our library10.1186/bcr80

  30. 30.

    Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 2006;38:1289-1297.

    Not in our library10.1038/ng1901

  31. 31.

    Carroll JS, Brown M. Estrogen receptor target gene: an evolving concept. Mol. Endocrinol. 2006;20:1707-1714.

    Not in our library10.1210/me.2005-0334

  32. 32.

    Liu Y, Gao H, Marstrand TT, Strom A, Valen E, Sandelin A, Gustafsson J-A, Dahlman-Wright K. The genome landscape of er{alpha}- and er{beta}-binding DNA regions. Proceedings of the National Academy of Sciences. 2008.

    Not in our library10.1073/pnas.0712085105

  33. 33.
    Whole-Genome Cartography of Estrogen Receptor α Binding Sites · 2007
    No notice
  34. 34.

    Kwon Y-S, Garcia-Bassets I, Hutt KR, Cheng CS, Jin M, Liu D, Benner C, Wang D, Ye Z, Bibikova M, Fan J-B, Duan L, Glass CK, Rosenfeld MG, Fu X-D. Sensitive chip-dsl technology reveals an extensive estrogen receptor {alpha}-binding program on human gene promoters. Proc. Natl. Acad. Sci. USA. 2007;104:4852-4857.

    Not in our library10.1073/pnas.0700715104

  35. 35.

    McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: Cellular and molecular biology. Endocr. Rev. 1999;20:321-344.

    Not in our library10.1210/edrv.20.3.0366

  36. 36.

    Bourdeau V, Deschenes J, Laperriere D, Aid M, White JH, Mader S. Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells. Nucleic Acids Res. 2008;36:76-93.

    Not in our library10.1093/nar/gkm945

  37. 37.

    Lannigan DA. Estrogen receptor phosphorylation. Steroids. 2003;68:1-9.

    Not in our library10.1016/s0039-128x(02)00110-1

  38. 38.

    Stenoien DL, Mancini MG, Patel K, Allegretto EA, Smith CL, Mancini MA. Subnuclear trafficking of estrogen receptor-alpha and steroid receptor coactivator-1. Mol. Endocrinol. 2000;14:518-534.

    Not in our library10.1210/mend.14.4.0436

  39. 39.

    Stenoien DL, Nye AC, Mancini MG, Patel K, Dutertre M, O'Malley BW, Smith CL, Belmont AS, Mancini MA. Ligand-mediated assembly and real-time cellular dynamics of estrogen receptor alpha-coactivator complexes in living cells. Mol. Cell. Biol. 2001;21:4404-4412.

    Not in our library10.1128/mcb.21.13.4404-4412.2001

  40. 40.

    Stenoien DL, Patel K, Mancini MG, Dutertre M, Smith CL, O'Malley BW, Mancini MA. Frap reveals that mobility of oestrogen receptor-alpha is ligand- and proteasome-dependent. Nat. Cell. Biol. 2001;3:15-23.

    Not in our library10.1038/35050515

  41. 41.

    Porter W, Wang F, Wang W, Duan R, Safe S. Role of estrogen receptor/sp1 complexes in estrogen-induced heat shock protein 27 gene expression. Mol. Endocrinol. 1996;10:1371-1378.

    Not in our library10.1210/mend.10.11.8923463

  42. 42.

    Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS. Differential ligand activation of estrogen receptors eralpha and erbeta at ap1 sites. Science. 1997;277:1508-1510.

    Not in our library10.1126/science.277.5331.1508

  43. 43.

    Klinge CM. Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000;65:227-251.

    Not in our library10.1016/s0039-128x(99)00107-5

  44. 44.

    Lonard DM, O'Malley BW. Nuclear receptor coregulators: Judges, juries, and executioners of cellular regulation. Mol. Cell. 2007;27:691-700.

    Not in our library10.1016/j.molcel.2007.08.012

  45. 45.

    Rosenfeld MG, Lunyak VV, Glass CK. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 2006;20:1405-1428.

    Not in our library10.1101/gad.1424806

  46. 46.

    Horwitz K, Jackson T, Bain D, Richer J, Takimoto G, Tung L. Nuclear receptor coactivators and corepressors. Mol. Endocrinol. 1996;10:1167-1177.

    Not in our library10.1210/mend.10.10.9121485

  47. 47.

    O'Malley BW, McKenna NJ. Editorial: coactivators and corepressors: what's in a name? Mol. Endocrinol. 2008;22:2213-2214.

    Not in our library10.1210/me.2008-0201

  48. 48.

    Peterson TJ, Karmakar S, Pace MC, Gao T, Smith CL. The silencing mediator of retinoic acid and thyroid hormone receptor (smrt) corepressor is required for full estrogen receptor {alpha} transcriptional activity. Mol. Cell. Biol. 2007;27:5933-5948.

    Not in our library10.1128/mcb.00237-07

  49. 49.

    Yang XJ, Seto E. Hats and hdacs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene. 2007;26:5310-5318.

    Not in our library10.1038/sj.onc.1210599

  50. 50.

    Privalsky ML. The role of corepressors in transcriptional regulation by nuclear hormone receptors. Annu. Rev. Physiol. 2004;66:315-360.

    Not in our library10.1146/annurev.physiol.66.032802.155556

  51. 51.

    Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr. Rev. 2004;25:45-71.

    Not in our library10.1210/er.2003-0023

  52. 52.

    Beato M, Candau R, Chavez S, Mows C, Truss M. Interaction of steroid hormone receptors with transcription factors involves chromatin remodelling. J. Steroid Biochem. Mol. Biol. 1996;56:47-59.

    Not in our library10.1016/0960-0760(95)00223-5

  53. 53.

    Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95:927-937.

    Not in our library10.1016/s0092-8674(00)81717-1

  54. 54.

    Smith CL, Nawaz Z, O'Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol. Endocrinol. 1997;11:657-666.

    Not in our library10.1210/mend.11.6.0009

  55. 55.

    Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2000;103:843-852.

    Not in our library10.1016/s0092-8674(00)00188-4

  56. 56.

    Jung DJ, Lee SK, Lee JW. Agonist-dependent repression mediated by mutant estrogen receptor alpha that lacks the activation function 2 core domain. J. Biol. Chem. 2001;276:37280-37283.

    Not in our library10.1074/jbc.m106860200

  57. 57.

    Shang Y, Brown M. Molecular determinants for the tissue specificity of serms. Science. 2002;295:2465-2468.

    Not in our library10.1126/science.1068537

  58. 58.

    Huang HJ, Norris JD, McDonnell DP. Identification of a negative regulatory surface within estrogen receptor alpha provides evidence in support of a role for corepressors in regulating cellular responses to agonists and antagonists. Mol. Endocrinol. 2002;16:1778-1792.

    Not in our library10.1210/me.2002-0089

  59. 59.

    Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, McDonnell DP. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology. 1999;140:5828-5840.

    Not in our library10.1210/endo.140.12.7164

  60. 60.

    Peekhaus N, Chang T, Hayes E, Wilkinson H, Mitra S, Schaeffer J, Rohrer S. Distinct effects of the antiestrogen faslodex on the stability of estrogen receptors-alpha and -beta in the breast cancer cell line mcf-7. J. Mol. Endocrinol. 2004;32:987-995.

    Not in our library10.1677/jme.0.0320987

  61. 61.

    Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr. Rev. 2002;23:665-686.

    Not in our library10.1210/er.2001-0045

  62. 62.

    Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 2006;20:1996-2009.

    Not in our library10.1210/me.2005-0525

  63. 63.

    Kim JK, Levin ER. Estrogen signaling in the cardiovascular system. Nucleic Recept. Signal. 2006;4:e013.

    Not in our library10.1621/nrs.04013

  64. 64.

    Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol. Endocrinol. 2005;19:1951-1959.

    Not in our library10.1210/me.2004-0390

  65. 65.

    Watson CS, Alyea RA, Jeng YJ, Kochukov MY. Nongenomic actions of low concentration estrogens and xenoestrogens on multiple tissues. Mol. Cell. Endocrinol. 2007;274:1-7.

    Not in our library10.1016/j.mce.2007.05.011

  66. 66.

    Razandi M, Pedram A, Levin ER. Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Mol. Endocrinol. 2000;14:1434-1447.

    Not in our library10.1210/mend.14.9.0526

  67. 67.

    Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, Adachi K, Tasaka K, Miyoshi E, Fujiwara N, Taniguchi N, Murata Y. Estrogen induces the akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J. Biol. Chem. 2001;276:3459-3467.

    Not in our library10.1074/jbc.m005036200

  68. 68.

    Monje P, Boland R. Expression and cellular localization of naturally occurring beta estrogen receptors in uterine and mammary cell lines. J. Cell. Biochem. 2002;86:136-144.

    Not in our library10.1002/jcb.10193

  69. 69.

    Chen DB, Bird IM, Zheng J, Magness RR. Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. Endocrinology. 2004;145:113-125.

    Not in our library10.1210/en.2003-0547

  70. 70.

    Belcher SM, Le HH, Spurling L, Wong JK. Rapid estrogenic regulation of extracellular signal- regulated kinase 1/2 signaling in cerebellar granule cells involves a g protein- and protein kinase a-dependent mechanism and intracellular activation of protein phosphatase 2a. Endocrinology. 2005;146:5397-5406.

    Not in our library10.1210/en.2005-0564

  71. 71.

    Mhyre AJ, Shapiro RA, Dorsa DM. Estradiol reduces non-classical transcription at cyclic adenosine 3',5'-monophosphate response elements in glioma cells expressing estrogen receptor alpha. Endocrinology. 2006;147:1796-1804.

    Not in our library10.1210/en.2005-1316

  72. 72.

    Simoncini T, Scorticati C, Mannella P, Fadiel A, Giretti MS, Fu X-D, Baldacci C, Garibaldi S, Caruso A, Fornari L, Naftolin F, Genazzani AR. Estrogen receptor {alpha} interacts with g{alpha}13 to drive actin remodeling and endothelial cell migration via the rhoa/rho kinase/moesin pathway. Mol. Endocrinol. 2006;20:1756-1771.

    Not in our library10.1210/me.2005-0259

  73. 73.

    Filardo E, Quinn J, Pang Y, Graeber C, Shaw S, Dong J, Thomas P. Activation of the novel estrogen receptor g protein-coupled receptor 30 (gpr30) at the plasma membrane. Endocrinology. 2007;148:3236-3245.

    Not in our library10.1210/en.2006-1605

  74. 74.

    Jaubert A-M, Mehebik-Mojaat N, Lacasa D, Sabourault D, Giudicelli Y, Ribiere C. Nongenomic estrogen effects on nitric oxide synthase activity in rat adipocytes. Endocrinology. 2007;148:2444-2452.

    Not in our library10.1210/en.2006-1329

  75. 75.

    Wang C, Prossnitz ER, Roy SK. G protein-coupled receptor 30 expression is required for estrogen stimulation of primordial follicle formation in the hamster ovary. Endocrinology. 2008;149:4452-4461.

    Not in our library10.1210/en.2008-0441

  76. 76.

    Graber R, Sumida C, Vallette G, Nunez EA. Rapid and long-term effects of 17 beta-estradiol on pip2-phospholipase c-specific activity of mcf-7 cells. Cell Signal. 1993;5:181-186.

    Not in our library10.1016/0898-6568(93)90069-x

  77. 77.
    Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium · 1999
    Not checked
  78. 78.

    Levin ER. Cellular functions of plasma membrane estrogen receptors. Steroids. 2002;67:471-475.

    Not in our library10.1016/s0039-128x(01)00179-9

  79. 79.

    Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER. Ers associate with and regulate the production of caveolin: Implications for signaling and cellular actions. Mol. Endocrinol. 2002;16:100-115.

    Not in our library10.1210/mend.16.1.0757

  80. 80.

    Song RX-D, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ. Linkage of rapid estrogen action to mapk activation by er{alpha}-shc association and shc pathway activation. Mol. Endocrinol. 2002;16:116-127.

    Not in our library10.1210/mend.16.1.0748

  81. 81.

    Razandi M, Alton G, Pedram A, Ghonshani S, Webb P, Levin ER. Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane. Mol. Cell. Biol. 2003;23:1633-1646.

    Not in our library10.1128/mcb.23.5.1633-1646.2003

  82. 82.

    Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 2003;278:2701-2712.

    Not in our library10.1074/jbc.m205692200

  83. 83.

    Bulayeva NN, Gametchu B, Watson CS. Quantitative measurement of estrogen-induced erk 1 and 2 activation via multiple membrane-initiated signaling pathways. Steroids. 2004;69:181-192.

    Not in our library10.1016/j.steroids.2003.12.003

  84. 84.

    Fernando RI, Wimalasena J. Estradiol abrogates apoptosis in breast cancer cells through inactivation of bad: ras-dependent nongenomic pathways requiring signaling through erk and akt. Mol. Biol. Cell. 2004;15:3266-3284.

    Not in our library10.1091/mbc.e03-11-0823

  85. 85.

    Razandi M, Pedram A, Merchenthaler I, Greene GL, Levin ER. Plasma membrane estrogen receptors exist and functions as dimers. Mol. Endocrinol. 2004;18:2854-2865.

    Not in our library10.1210/me.2004-0115

  86. 86.

    Razandi M, Pedram A, Rosen EM, Levin ER. Brca1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Mol. Cell. Biol. 2004;24:5900-5913.

    Not in our library10.1128/mcb.24.13.5900-5913.2004

  87. 87.

    Santen RJ, Song RX, Zhang Z, Yue W, Kumar R. Adaptive hypersensitivity to estrogen: mechanism for sequential responses to hormonal therapy in breast cancer. Clin. Cancer Res. 2004;10:337S-345S.

    Not in our library10.1158/1078-0432.ccr-031207

  88. 88.

    Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, Baldacci C, Genazzani AR. Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology. 2004;145:5745-5756.

    Not in our library10.1210/en.2004-0510

  89. 89.

    Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ. The role of shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane. Proc. Natl. Acad Sci. USA. 2004;101:2076-2081.

    Not in our library10.1073/pnas.0308334100

  90. 90.

    Toran-Allerand CD. Minireview: a plethora of estrogen receptors in the brain: Where will it end? Endocrinology. 2004;145:1069-1074.

    Not in our library10.1210/en.2003-1462

  91. 91.

    Pietras RJ, Marquez DC, Chen HW, Tsai E, Weinberg O, Fishbein M. Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids. 2005;70:372-381.

    Not in our library10.1016/j.steroids.2005.02.017

  92. 92.

    Watson CS, Bulayeva NN, Wozniak AL, Finnerty CC. Signaling from the membrane via membrane estrogen receptor-[alpha]: Estrogens, xenoestrogens, and phytoestrogens. Steroids. 2005;70:364-371.

    Not in our library10.1016/j.steroids.2005.03.002

  93. 93.

    Cui Y, Parra I, Zhang M, Hilsenbeck SG, Tsimelzon A, Furukawa T, Horii A, Zhang Z-Y, Nicholson RI, Fuqua SAW. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Res. 2006;66:5950-5959.

    Not in our library10.1158/0008-5472.can-05-3243

  94. 94.

    Riggins RB, Thomas KS, Ta HQ, Wen J, Davis RJ, Schuh NR, Donelan SS, Owen KA, Gibson MA, Shupnik MA, Silva CM, Parsons SJ, Clarke R, Bouton AH. Physical and functional interactions between cas and c-src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Cancer Res. 2006;66:7007-7015.

    Not in our library10.1158/0008-5472.can-05-3952

  95. 95.

    Greger JG, Fursov N, Cooch N, McLarney S, Freedman LP, Edwards DP, Cheskis BJ. Phosphorylation of mnar promotes estrogen activation of phosphatidylinositol 3-kinase. Mol. Cell. Biol. 2007;27:1904-1913.

    Not in our library10.1128/mcb.01732-06

  96. 96.

    Song RXD, Zhang Z, Chen Y, Bao Y, Santen RJ. Estrogen signaling via a linear pathway involving insulin-like growth factor i receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in mcf-7 breast cancer cells. Endocrinology. 2007;148:4091-4101.

    Not in our library10.1210/en.2007-0240

  97. 97.

    Stoica GE, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB, Stoica A. Estradiol rapidly activates akt via the erbb2 signaling pathway. Mol. Endocrinol. 2003;17:818-830.

    Not in our library10.1210/me.2002-0330

  98. 98.

    Rajhans R, Nair S, Holden AH, Kumar R, Tekmal RR, Vadlamudi RK. Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor. Cancer Res. 2007;67:5505-5512.

    Not in our library10.1158/0008-5472.can-06-3647

  99. 99.

    Ghisletti S, Meda C, Maggi A, Vegeto E. 17{beta}-estradiol inhibits inflammatory gene expression by controlling nf-{kappa}b intracellular localization. Mol. Cell. Biol. 2005;25:2957-2968.

    Not in our library10.1128/mcb.25.8.2957-2968.2005

  100. 100.

    Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial no synthase by estrogen receptor {alpha}. Proc. Natl. Acad Sci. USA. 2004.

    Not in our library10.1073/pnas.0407492101

  101. 101.

    Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, Jove R, Nicosia SV, Cheng JQ. Activation of phosphatidylinositol 3-kinase/akt pathway by androgen through interaction of p85alpha, androgen receptor, and src. J. Biol. Chem. 2003;278:42992-43000.

    Not in our library10.1074/jbc.m306295200

  102. 102.

    Kinoshita Y, Chen S. Induction of aromatase (cyp19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. Cancer Res. 2003;63:3546-3555.

    Not in our library

  103. 103.

    Pietras RJ, Szego CM. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature. 1977;265:69-72.

    Not in our library10.1038/265069a0

  104. 104.

    Watson CS, Campbell CH, Gametchu B. The dynamic and elusive membrane estrogen receptor-alpha. Steroids. 2002;67:429-437.

    Not in our library10.1016/s0039-128x(01)00172-6

  105. 105.

    Sheldahl LC, Shapiro RA, Bryant DN, Koerner IP, Dorsa DM. Estrogen induces rapid translocation of estrogen receptor [beta], but not estrogen receptor [alpha], to the neuronal plasma membrane. Neuroscience. 2008;153:751-761.

    Not in our library10.1016/j.neuroscience.2008.02.035

  106. 106.

    Murphy E, Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc. Res. 2007;75:478-486.

    Not in our library10.1016/j.cardiores.2007.03.025

  107. 107.

    Murphy E, Steenbergen C. Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart Fail Rev. 2007;12:293-300.

    Not in our library10.1007/s10741-007-9035-0

  108. 108.

    Subah Packer C. Estrogen protection, oxidized ldl, endothelial dysfunction and vasorelaxation in cardiovascular disease: New insights into a complex issue. Cardiovasc. Res. 2007;73:6-7.

    Not in our library10.1016/j.cardiores.2006.11.013

  109. 109.

    Joy S, Siow RCM, Rowlands DJ, Becker M, Wyatt AW, Aaronson PI, Coen CW, Kallo I, Jacob R, Mann GE. The isoflavone equol mediates rapid vascular relaxation: Ca2+-independent activation of endothelial nitric-oxide synthase/hsp90 involving erk1/2 and akt phosphorylation in human endothelial cells. J. Biol. Chem. 2006;281:27335-27345.

    Not in our library10.1074/jbc.m602803200

  110. 110.

    Kiss AL, Turi A, Mullner N, Kovacs E, Botos E, Greger A. Oestrogen-mediated tyrosine phosphorylation of caveolin-1 and its effect on the oestrogen receptor localisation: an in vivo study. Mol. Cell. Endocrinol. 2005;245:128-137.

    Not in our library10.1016/j.mce.2005.11.005

  111. 111.

    Wyckoff MH, Chambliss KL, Mineo C, Yuhanna IS, Mendelsohn ME, Mumby SM, Shaul PW. Plasma membrane estrogen receptors are coupled to endothelial nitric-oxide synthase through galpha(i). J. Biol. Chem. 2001;276:27071-27076.

    Not in our library10.1074/jbc.m100312200

  112. 112.

    Li L, Haynes MP, Bender JR. Plasma membrane localization and function of the estrogen receptor alpha variant (er46) in human endothelial cells. Proc. Natl. Acad. Sci. USA. 2003;100:4807-4812.

    Not in our library10.1073/pnas.0831079100

  113. 113.

    Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. Spalmitoylation modulates human estrogen receptor-alpha functions. Biochem. Biophys. Res. Commun. 2004;316:878-883.

    Not in our library10.1016/j.bbrc.2004.02.129

  114. 114.

    Pedram A, Razandi M, Sainson RCA, Kim JK, Hughes CC, Levin ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J. Biol. Chem. 2007;282:22278-22288.

    Not in our library10.1074/jbc.m611877200

  115. 115.

    Moriarty K, Kim KH, Bender JR. Estrogen receptor-mediated rapid signaling. Endocrinology. 2006;147:5557-5563.

    Not in our library10.1210/en.2006-0729

  116. 116.

    Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis BJ. Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with src/erk phosphorylation cascade. Proc. Natl. Acad. Sci. USA. 2002;99:14783-14788.

    Not in our library10.1073/pnas.192569699

  117. 117.

    Edwards DP, Boonyaratanakornkit V. Rapid extranuclear signaling by the estrogen receptor (er): Mnar couples er and src to the map kinase signaling pathway. Mol. Interv. 2003;3:12-15.

    Not in our library10.1124/mi.3.1.12

  118. 118.

    Barletta F, Wong CW, McNally C, Komm BS, Katzenellen-bogen B, Cheskis BJ. Characterization of the interactions of estrogen receptor and mnar in the activation of csrc. Mol. Endocrinol. 2004;18:1096-1108.

    Not in our library10.1210/me.2003-0335

  119. 119.

    Cheskis BJ. Regulation of cell signalling cascades by steroid hormones. J. Cell Biochem. 2004;93:20-27.

    Not in our library10.1002/jcb.20180

  120. 120.

    Mishra SK, Balasenthil S, Nguyen D, Vadlamudi RK. Cloning and functional characterization of pelp1/mnar promoter. Gene. 2004;330:115-122.

    Not in our library10.1016/j.gene.2004.01.011

  121. 121.

    Mishra SK, Talukder AH, Gururaj AE, Yang Z, Singh RR, Mahoney MG, Franci C, Vadlamudi RK, Kumar R. Upstream determinants of estrogen receptor-{alpha} regulation of metastatic tumor antigen 3 pathway. J. Biol. Chem. 2004;279:32709-32715.

    Not in our library10.1074/jbc.m402942200

  122. 122.

    Nair SS, Mishra SK, Yang Z, Balasenthil S, Kumar R, Vadlamudi RK. Potential role of a novel transcriptional coactivator pelp1 in histone h1 displacement in cancer cells. Cancer Res. 2004;64:6416-6423.

    Not in our library10.1158/0008-5472.can-04-1786

  123. 123.

    Kim KH, Bender JR. Rapid, estrogen receptor-mediated signaling: Why is the endothelium so special? Sci. STKE. 2005;2005:pe28.

    Not in our library10.1126/stke.2882005pe28

  124. 124.

    Greger JG, Guo Y, Henderson R, Ross JF, Cheskis BJ. Characterization of mnar expression. Steroids. 2006;71:317-322.

    Not in our library10.1016/j.steroids.2005.09.016

  125. 125.

    Li L, Hisamoto K, Kim KH, Haynes MP, Bauer PM, San-jay A, Collinge M, Baron R, Sessa WC, Bender JR. Variant estrogen receptor c-src molecular interdependence and c-src structural requirements for endothelial no synthase activation. Proc. Natl. Acad. Sci. 2007;104:16468-16473.

    Not in our library10.1073/pnas.0704315104

  126. 126.

    Marquez-Garban DC, Chen H-W, Fishbein MC, Goodglick L, Pietras RJ. Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids. 2007;72:135-143.

    Not in our library10.1016/j.steroids.2006.11.019

  127. 127.

    Cheskis BJ, Greger J, Cooch N, McNally C, McLarney S, Lam H-S, Rutledge S, Mekonnen B, Hauze D, Nagpal S, Freedman LP. Mnar plays an important role in era activation of Src/MAPK and pi3k/Akt signaling pathways. Steroids. 2008;73(9-10):901-905.

    Not in our library10.1016/j.steroids.2007.12.028

  128. 128.

    Rajhans R, Nair HB, Nair SS, Cortez V, Ikuko K, Kirma NB, Zhou D, Holden AE, Brann DW, Chen S, Tekmal RR, Vadlamudi RK. Modulation of in situ estrogen synthesis by proline-, glutamic acid-, and leucine-rich protein-1: Potential estrogen receptor autocrine signaling loop in breast cancer cells. Mol. Endocrinol. 2008;22:649-664.

    Not in our library10.1210/me.2007-0350

  129. 129.

    Hisamoto K, Bender JR. Vascular cell signaling by membrane estrogen receptors. Steroids. 2005;70:382-387.

    Not in our library10.1016/j.steroids.2005.02.011

  130. 130.

    Flototto T, Niederacher D, Hohmann D, Heimerzheim T, Dall P, Djahansouzi S, Bender HG, Hanstein B. Molecular mechanism of estrogen receptor (er)[alpha]-specific, estradiol-dependent expression of the progesterone receptor (pr) b-isoform. J. Steroid Biochem. Mol. Biol. 2004;88:131-142.

    Not in our library10.1016/j.jsbmb.2003.11.004

  131. 131.

    Filardo EJ. Epidermal growth factor receptor (egfr) transactivation by estrogen via the g-protein-coupled receptor, gpr30: a novel signaling pathway with potential significance for breast cancer. J. Steroid Biochem. Mol. Biol. 2002;80:231-238.

    Not in our library10.1016/s0960-0760(01)00190-x

  132. 132.

    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307:1625-1630.

    Not in our library10.1126/science.1106943

  133. 133.

    Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a g protein in human breast cancer cells. Endocrinology. 2005;146:624-632.

    Not in our library10.1210/en.2004-1064

  134. 134.

    Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem. Biophys. Res. Commun. 2006;346:904-910.

    Not in our library10.1016/j.bbrc.2006.05.191

  135. 135.

    Wang C, Dehghani B, Magrisso IJ, Rick EA, Bonhomme E, Cody DB, Elenich LA, Subramanian S, Murphy SJ, Kelly MJ, Rosenbaum JS, Vandenbark AA, Offner H. Gpr30 contributes to estrogen-induced thymic atrophy. Mol. Endocrinol. 2008;22:636-648.

    Not in our library10.1210/me.2007-0359

  136. 136.

    Prossnitz ER, Oprea TI, Sklar LA, Arterburn JB. The ins and outs of gpr30: a transmembrane estrogen receptor. J. Steroid Biochem. Mol. Biol. 2008;109:350-353.

    Not in our library10.1016/j.jsbmb.2008.03.006

  137. 137.

    Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier K-H. Gpr30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology. 2008;149(10):4846-4856.

    Not in our library10.1210/en.2008-0269

  138. 138.

    Filardo EJ, Quinn JA, Sabo E. Association of the membrane estrogen receptor, gpr30, with breast tumor metastasis and transactivation of the epidermal growth factor receptor. Steroids. 2008;73:870-873.

    Not in our library10.1016/j.steroids.2007.12.025

  139. 139.

    Sakamoto H, Matsuda K-i, Hosokawa K, Nishi M, Morris JF, Prossnitz ER, Kawata M. Expression of g protein-coupled receptor-30, a g protein-coupled membrane estrogen receptor, in oxytocin neurons of the rat paraventricular and supraoptic nuclei. Endocrinology. 2007;148:5842-5850.

    Not in our library10.1210/en.2007-0436

  140. 140.

    Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor gpr30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 2006;102:175-179.

    Not in our library10.1016/j.jsbmb.2006.09.017

  141. 141.

    Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM, Sabo E. Distribution of gpr30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin. Cancer Res. 2006;12:6359-6366.

    Not in our library10.1158/1078-0432.ccr-06-0860

  142. 142.

    ENCODE, project, consortium. Identification and analysis of functional elements in 1% of the human genome by the encode pilot project. Nature. 2007;447:799-816.

    Not in our library10.1038/nature05874

  143. 143.

    Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007;316:1484-1488.

    Not in our library10.1126/science.1138341

  144. 144.

    Pennisi E. Genomics: DNA study forces rethink of what it means to be a gene. Science. 2007;316:1556-1557.

    Not in our library10.1126/science.316.5831.1556

  145. 145.

    Amaral PP, Dinger ME, Mercer TR, Mattick JS. The eukaryotic genome as an rna machine. Science. 2008;319:1787-1789.

    Not in our library10.1126/science.1155472

  146. 146.

    Ambros V. The evolution of our thinking about microRNAs. Nat. Med. 2008;14:1036-1040.

    Not in our library10.1038/nm1008-1036

  147. 147.

    Ruvkun G. The perfect storm of tiny rnas. Nat. Med. 2008;14:1041-1045.

    Not in our library10.1038/nm1008-1041

  148. 148.

    Baulcombe DC. Short silencing RNA: The dark matter of genetics? Cold Spring Harb. Symp. Quant. Biol. 2006;71:13-20.

    Not in our library10.1101/sqb.2006.71.052

  149. 149.

    Saini HK, Griffiths-Jones S, Enright AJ. Genomic analysis of human microRNA transcripts. Proc. Natl. Acad. Sci. 2007;104:17719-17724.

    Not in our library10.1073/pnas.0703890104

  150. 150.

    Verghese ET, Hanby AM, Speirs V, Hughes TA. Small is beautiful: microRNAs and breast cancer-where are we now? J. Pathol. 2008;215:214-221.

    Not in our library10.1002/path.2359

  151. 151.

    Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006;20:2202-2207.

    Not in our library10.1101/gad.1444406

  152. 152.

    Hock J, Meister G. The argonaute protein family. Genome Biol. 2008;9:210.

    Not in our library10.1186/gb-2008-9-2-210

  153. 153.

    Pasquinelli AE, Hunter S, Bracht J. MicroRNAs: a developing story. Curr. Opin. Genet. Dev. 2005;15:200-205.

    Not in our library10.1016/j.gde.2005.01.002

  154. 154.

    Sen GL, Blau HM. A brief history of rnai: the silence of the genes. FASEB J. 2006;20:1293-1299.

    Not in our library10.1096/fj.06-6014rev

  155. 155.

    Berkhout B, Jeang K-T. Riscy business: MicroRNAs, pathogenesis, and viruses. J. Biol. Chem. 2007;282:26641-26645.

    Not in our library10.1074/jbc.r700023200

  156. 156.

    Cuellar TL, McManus MT. MicroRNAs and endocrine biology. J. Endocrinol. 2005;187:327-332.

    Not in our library10.1677/joe.1.06426

  157. 157.

    Chendrimada TP, Finn KJ, Ji X, Baillat D, Gregory RI, Liebhaber SA, Pasquinelli AE, Shiekhattar R. MicroRNA silencing through risc recruitment of eif6. Nature. 2007;447:823-828.

    Not in our library10.1038/nature05841

  158. 158.

    Perron MP, Provost P. Protein interactions and complexes in human microRNA biogenesis and function. Front. Biosci. 2008;13:2537-2547.

    Not in our library10.2741/2865

  159. 159.

    Friedman RC, Farh KK-H, Burge CB, Bartel D. Most mammalian mrnas are conserved targets of microRNAs. Genome Res. 2008.

    Not in our library10.1101/gr.082701.108

  160. 160.

    Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931-1934.

    Not in our library10.1126/science.1149460

  161. 161.

    Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T. MicroRNA regulates the expression of human cytochrome p450 1b1. Cancer Res. 2006;66:9090-9098.

    Not in our library10.1158/0008-5472.can-06-1403

  162. 162.

    Adams BD, Furneaux H, White BA. The micro-ribonucleic acid (mirna) mir-206 targets the human estrogen receptor-{alpha} (er{alpha}) and represses er{alpha} messenger rna and protein expression in breast cancer cell lines. Mol. Endocrinol. 2007;21:1132-1147.

    Not in our library10.1210/me.2007-0022

  163. 163.

    Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY. MicroRNA-34b and microRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. Cancer Res. 2007;67:8433-8438.

    Not in our library10.1158/0008-5472.can-07-1585

  164. 164.

    Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR, Israel MA. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007;67:2456-2468.

    Not in our library10.1158/0008-5472.can-06-2698

  165. 165.

    Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu C-G, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, Croce CM, Bolondi L, Negrini M. Cyclin g1 is a target of mir-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67:6092-6099.

    Not in our library10.1158/0008-5472.can-06-4607

  166. 166.

    Hurteau GJ, Carlson JA, Spivack SD, Brock GJ. Overexpression of the microRNA hsa-mir-200c leads to reduced expression of transcription factor 8 and increased expression of e-cadherin. Cancer Res. 2007;67:7972-7976.

    Not in our library10.1158/0008-5472.can-07-1058

  167. 167.

    Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, Wilson M, Wang X, Shelton J, Shingara J, Chin L, Brown D, Slack FJ. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 2007;67:7713-7722.

    Not in our library10.1158/0008-5472.can-07-1083

  168. 168.

    Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, Casado S, Suarez-Gauthier A, Sanchez-Cespedes M, Gitt A, Spiteri I, Das PP, Caldas C, Miska E, Esteller M. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007;67:1424-1429.

    Not in our library10.1158/0008-5472.can-06-4218

  169. 169.

    Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the pten tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647-658.

    Not in our library10.1053/j.gastro.2007.05.022

  170. 170.

    Osada H, Takahashi T. MicroRNAs in biological processes and carcinogenesis. Carcinogenesis. 2007;28:2-12.

    Not in our library10.1093/carcin/bgl185

  171. 171.

    Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP, Krueger LJ. MicroRNA let-7a down-regulates myc and reverts myc-induced growth in burkitt lymphoma cells. Cancer Res. 2007;67:9762-9770.

    Not in our library10.1158/0008-5472.can-07-2462

  172. 172.

    Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F, Ferbeyre G, Chartrand P. An e2f/mir-20a autoregulatory feedback loop. J. Biol. Chem. 2007;282:2135-2143.

    Not in our library10.1074/jbc.m608939200

  173. 173.

    Thai T-H, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604-608.

    Not in our library10.1126/science.1141229

  174. 174.

    Woods K, Thomson JM, Hammond SM. Direct regulation of an oncogenic micro-rna cluster by e2f transcription factors. J. Biol. Chem. 2007;282:2130-2134.

    Not in our library10.1074/jbc.c600252200

  175. 175.

    Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis: a primer. Am. J. Pathol. 2007;171:728-738.

    Not in our library10.2353/ajpath.2007.070070

  176. 176.
    Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer · 2007
    No notice
  177. 177.

    Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA. 2006;103:2257-2261.

    Not in our library10.1073/pnas.0510565103

  178. 178.

    Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'Brien-Jenkins A, Katsaros D, Hat-zigeorgiou A, Gimotty PA, Weber BL, Coukos G. MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc. Natl. Acad. Sci. USA. 2006;103:9136-9141.

    Not in our library10.1073/pnas.0508889103

  179. 179.

    Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis. 2000;21:427-433.

    Not in our library10.1093/carcin/21.3.427

  180. 180.

    Russo J, Tahin Q, Lareef MH, Hu YF, Russo IH. Neoplastic transformation of human breast epithelial cells by estrogens and chemical carcinogens. Environ. Mol. Mutagen. 2002;39:254-263.

    Not in our library10.1002/em.10052

  181. 181.

    Russo J, Lareef MH, Tahin Q, Hu YF, Slater C, Ao X, Russo IH. 17beta-estradiol is carcinogenic in human breast epithelial cells. J. Steroid Biochem. Mol. Biol. 2002;80:149-162.

    Not in our library10.1016/s0960-0760(01)00183-2

  182. 182.

    Russo J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, Garber J, Russo IH. 17-beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. FASEB J. 2006;20:1622-1634.

    Not in our library10.1096/fj.05-5399com

  183. 183.

    Wiseman RA. Breast cancer: critical data analysis concludes that estrogens are not the cause, however lifestyle changes can alter risk rapidly. J. Clin. Epidemiol. 2004;57:766-772.

    Not in our library10.1016/j.jclinepi.2003.10.017

  184. 184.

    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029-6033.

    Not in our library10.1158/0008-5472.can-05-0137

  185. 185.

    Hammond SM. MicroRNAs as oncogenes. Curr. Opin. Genet. Dev. 2005.

    Not in our library10.1016/j.gde.2005.12.005

  186. 186.

    Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T. A polycistronic microRNA cluster, mir-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628-9632.

    Not in our library10.1158/0008-5472.can-05-2352

  187. 187.

    Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ. Ras is regulated by the let-7 microRNA family. Cell. 2005;120:635-647.

    Not in our library10.1016/j.cell.2005.01.014

  188. 188.

    Diederichs S, Haber DA. Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing. Cancer Res. 2006;66:6097-6104.

    Not in our library10.1158/0008-5472.can-06-0537

  189. 189.

    Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 2006;66:1277-1281.

    Not in our library10.1158/0008-5472.can-05-3632

  190. 190.

    Giannakakis A, Coukos G, Hatzigeorgiou A, Sandaltzopoulos R, Zhang L. miRNA genetic alterations in human cancers. Expert Opin. Biol. Ther. 2007;7:1375-1386.

    Not in our library10.1517/14712598.7.9.1375

  191. 191.

    Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, Wells W, Kauppinen S, Cole CN. Altered microRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res. 2007;67:11612-11620.

    Not in our library10.1158/0008-5472.can-07-5019

  192. 192.
    Computational analysis of biological functions and pathways collectively targeted by co-expressed microRNAs in cancer · 2007
    Not checked
  193. 193.

    Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH, Li Y. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 2008;27:4373-4379.

    Not in our library10.1038/onc.2008.72

  194. 194.

    Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of aib1 mRNA. Mol. Cell. Biol. 2006;26:8191-8201.

    Not in our library10.1128/mcb.00242-06

  195. 195.

    Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of erbb2 and erbb3 by enforced expression of micro-RNA mir-125a or mir-125b. J. Biol. Chem. 2007;282:1479-1486.

    Not in our library10.1074/jbc.m609383200

  196. 196.

    Creighton CJ, Nagaraja AK, Hanash SM, Matzuk MM, Gunaratne PH. A bioinformatics tool for linking gene expression profiling results with public databases of microRNA target predictions. RNA. 2008;14:2290-2296.

    Not in our library10.1261/rna.1188208

  197. 197.

    Cohen A, Shmoish M, Levi L, Cheruti U, Levavi-Sivan B, Lubzens E. Alterations in micro-ribonucleic acid expression profiles reveal a novel pathway for estrogen regulation. Endocrinology. 2008;149:1687-1696.

    Not in our library10.1210/en.2007-0969

  198. 198.

    Kovalchuk O, Tryndyak VP, Montgomery B, Boyko A, Kutanzi K, Zemp F, Warbritton AR, Latendresse JR, Kovalchuk I, Beland FA, Pogribny IP. Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications and aberrant microRNA expression. Cell Cycle. 2007;6:2010-2018.

    Not in our library10.4161/cc.6.16.4549

  199. 199.

    Dai R, Phillips RA, Zhang Y, Khan D, Crasta O, Ahmed SA. Suppression of lps-induced ifn{gamma} and nitric oxide in splenic lymphocytes by select estrogen-regulated mirna: a novel mechanism of immune modulation. Blood. 2008;112(12):4591-4597.

    Not in our library10.1182/blood-2008-04-152488

  200. 200.

    Hong X, Luense LJ, McGinnis LK, Nothnick WB, Christen-son LK. Dicer1 is essential for female fertility and normal development of the female reproductive system. Endocrinology. 2008;149(12):6207-6212.

    Not in our library10.1210/en.2008-0294

  201. 201.

    Carletti MZ, Christenson LK. MicroRNA in the ovary and female reproductive tract. J. Anim Sci. 2008.

    Not in our library10.2527/jas.2008-1331

  202. 202.

    Hu S-J, Ren G, Liu J-L, Zhao Z-A, Yu Y-S, Su R-W, Ma X-H, Ni H, Lei W, Yang Z-M. MicroRNA expression and regulation in mouse uterus during embryo implantation. J. Biol. Chem. 2008;283:23473-23484.

    Not in our library10.1074/jbc.m800406200

  203. 203.

    Harris HA, Katzenellenbogen JA, Katzenellenbogen BS. Characterization of the biological roles of the estrogen receptors, eralpha and erbeta, in estrogen target tissues in vivo through the use of an eralpha-selective ligand. Endocrinology. 2002;143:4172-4177.

    Not in our library10.1210/en.2002-220403

  204. 204.

    Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA. Estrogen receptor-beta potency-selective ligands: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J. Med. Chem. 2001;44:4230-4251.

    Not in our library10.1021/jm010254a

  205. 205.

    Ferguson AT, Lapidus RG, Baylin SB, Davidson NE. Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res. 1995;55:2279-2283.

    Not in our library

  206. 206.

    Yang X, Ferguson AT, Nass SJ, Phillips DL, Butash KA, Wang SM, Herman JG, Davidson NE. Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. Cancer Res. 2000;60:6890-6894.

    Not in our library

  207. 207.

    Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE. Synergistic activation of functional estrogen receptor (er)-alpha by DNA methyltransferase and histone deacetylase inhibition in human er-alpha-negative breast cancer cells. Cancer Res. 2001;61:7025-7029.

    Not in our library

  208. 208.

    Sharma D, Blum J, Yang X, Beaulieu N, Macleod AR, Davidson NE. Release of methyl cpg binding proteins and histone deacetylase 1 from the estrogen receptor {alpha} (er) promoter upon reactivation in er-negative human breast cancer cells. Mol. Endocrinol. 2005;19:1740-1751.

    Not in our library10.1210/me.2004-0011

  209. 209.

    Sharma D, Saxena NK, Davidson NE, Vertino PM. Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated er recruits distinctive corepressor complexes. Cancer Res. 2006;66:6370-6378.

    Not in our library10.1158/0008-5472.can-06-0402

  210. 210.

    Pan Q, Luo X, Chegini N. Differential expression of microRNAs in myometrium and leiomyomas and regulation by ovarian steroids. J. Cell. Mol. Med. 2008;12:227-240.

    Not in our library10.1111/j.1582-4934.2007.00207.x

  211. 211.

    Kondo N, Toyama T, Sugiura H, Fujii Y, Yamashita H. Mir-206 expression is down-regulated in estrogen receptor {alpha}-positive human breast cancer. Cancer Res. 2008;68:5004-5008.

    Not in our library10.1158/0008-5472.can-08-0180

  212. 212.

    Zhao J-J, Lin J, Yang H, Kong W, He L, Ma X, Coppola D, Cheng JQ. MicroRNA-221/222 negatively regulates eralpha and associates with tamoxifen resistance in breast cancer. J. Biol. Chem. 2008;283:31079-31086.

    Not in our library10.1074/jbc.m806041200

  213. 213.

    Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol. Cancer Ther. 2008;7:464-473.

    Not in our library10.1158/1535-7163.mct-07-2272

  214. 214.

    Buchan JR, Parker R. Molecular biology: the two faces of mirna. Science. 2007;318:1877-1878.

    Not in our library10.1126/science.1152623

  215. 215.

    Klinge CM, Wickramasinghe NS, Ivanova MM, Dougherty SM. Resveratrol stimulates nitric oxide production by increasing estrogen receptor {alpha}-src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J. 2008;22:2185-2197.

    Not in our library10.1096/fj.07-103366

  216. 216.

    Chambliss KL, Simon L, Yuhanna IS, Mineo C, Shaul PW. Dissecting the basis of nongenomic activation of endothelial nitric oxide synthase by estradiol: role of eralpha domains with known nuclear functions. Mol. Endocrinol. 2005;19:277-289.

    Not in our library10.1210/me.2004-0008

  217. 217.

    Klinge CM. Estrogenic control of mitochondrial function and biogenesis. J. Cell. Biochem. 2008;105:1342-1351.

    Not in our library10.1002/jcb.21936

  218. 218.

    Chen J-Q, Russo PA, Cooke C, Russo IH, Russo J. Er[beta] shifts from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins. Biochimica et Biophysica Acta (BBA) - Mol. Cell Res. 2007;1773:1732-1746.

    Not in our library10.1016/j.bbamcr.2007.05.008

  219. 219.

    Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the g2-m checkpoint in mda-mb-231 breast cancer cells. Cancer Res. 2007;67:11001-11011.

    Not in our library10.1158/0008-5472.can-07-2416

  220. 220.

    Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E. Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131:1109-1123.

    Not in our library10.1016/j.cell.2007.10.054

  221. 221.

    Tsang WP, Kwok TT. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis. 2008;13(10):1215-22.

    Not in our library10.1007/s10495-008-0256-z

  222. 222.

    Ovcharenko D, Kelnar K, Johnson C, Leng N, Brown D. Genome-scale microRNA and small interfering rna screens identify small RNA modulators of trail-induced apoptosis pathway. Cancer Res. 2007;67:10782-10788.

    Not in our library10.1158/0008-5472.can-07-1484

  223. 223.

    Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A, Wang H, Sun H, Volinia S, Alder H, Calin GA, Liu CG, Andreeff M, Croce CM. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene. 2007;26:4148-4157.

    Not in our library10.1038/sj.onc.1210186

  224. 224.

    Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, Kobayashi SV, Lim L, Burchard J, Jackson AL, Linsley PS, Cleary MA. MicroRNAs in the mir-106b family regulate p21/cdkn1a and promote cell cycle progression. Mol. Cell. Biol. 2008;28:2167-2174.

    Not in our library10.1128/mcb.01977-07

  225. 225.

    Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006;66:7390-7394.

    Not in our library10.1158/0008-5472.can-06-0800

  226. 226.

    Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu C-g, Kipps TJ, Negrini M, Croce CM. Mir-15 and mir-16 induce apoptosis by targeting bcl2. Proc. Natl. Acad. Sci. 2005;102:13944-13949.

    Not in our library10.1073/pnas.0506654102

  227. 227.

    Linsley PS, Schelter J, Burchard J, Kibukawa M, Martin MM, Bartz SR, Johnson JM, Cummins JM, Raymond CK, Dai H, Chau N, Cleary M, Jackson AL, Carleton M, Lim L. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol. Cell. Biol. 2007;27:2240-2252.

    Not in our library10.1128/mcb.02005-06

  228. 228.

    Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J, Xing R, Sun Z, Zheng X. Mir-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res. 2008;36:5391-5404.

    Not in our library10.1093/nar/gkn522

  229. 229.

    Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu C-G, Croce CM, Negrini M, Calin GA, Ivan M. A microRNA signature of hypoxia. Mol. Cell. Biol. 2007;27:1859-1867.

    Not in our library10.1128/mcb.01395-06

  230. 230.

    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The mir-200 family and mir-205 regulate epithelial to mesenchymal transition by targeting zeb1 and sip1. Nat. Cell Biol. 2008;10:593-601.

    Not in our library10.1038/ncb1722

  231. 231.

    Pan Q, Luo X, Toloubeydokhti T, Chegini N. The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol. Hum. Reprod. 2007;13:797-806.

    Not in our library10.1093/molehr/gam063

  232. 232.
    The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition · 2008
    No notice
  233. 233.

    Yan L-X, Huang X-F, Shao Q, Huang M-Y, Deng L, Wu Q-L, Zeng Y-X, Shao J-Y. MicroRNA mir-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA. 2008;14:2348-2360.

    Not in our library10.1261/rna.1034808

  234. 234.

    Wang CH, Lee DY, Deng Z, Jeyapalan Z, Lee SC, Kahai S, Lu WY, Zhang Y, Yang BB. MicroRNA mir-328 regulates zonation morphogenesis by targeting cd44 expression. PLoS ONE. 2008;3:e2420.

    Not in our library10.1371/journal.pone.0002420

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