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PubMed2005

Anti-growth factor activities of benzothiophenes in human breast cancer cells.

We have tested the effects of two Eli-Lilly compounds, LY 117, 018 and raloxifene, on E2-regulated and IGF-I-induced proliferation or AP-1 activity in human breast cancer cells. We now demonstrate that both molecules have strong antiestrogenic and anti-growth factor inhibitory effects in MCF7 cells. They were as potent as ICI 182, 780 and more efficient than OH-Tam to prevent estradiol action whereas their inhibition on IGF-I stimulation was less than with ICI 182, 780 and equivalent to that of OH-Tam. Moreover, raloxifene was the most efficient molecule to prevent IGF-I-induced AP-1 activity, with a significant effect observed with a concentration as low as 5 x 10(-11)M in the presence of IGF-I alone. Similar dose-response curves were obtained with a combined treatment of IGF-I and E2 with a 2log shift. Their action on IGF-I-induced proliferation was completely abrogated in MCF7 transfectants in which the expression of an antiestrogen-regulated protein tyrosine phosphatase, PTPL1, was abolished by antisense RNA transfection. Accordingly, they were both able to dose-dependently regulate the expression of PTPL1 and to interfere with the PI3-K/Akt pathway by drastically decreasing Akt phosphorylation exclusively in wild-type PTPL1 expressing cells. Our data altogether demonstrate that raloxifene has a potent inhibitory effect on IGF-I action, with a drastic effect on AP-1 triggered responses as well as on Akt phosphorylation, suggesting that it might be a useful therapeutic agent in tumors in which these signalling pathways become constitutively active.

Breast Neoplasms↗
PubMed2005

Role of the proteasome in the regulation of estrogen receptor alpha turnover and function in MCF-7 breast carcinoma cells.

Estrogen receptor alpha (ER) turnover in MCF-7 cells was assessed by pulse chase analysis and measurement of ER steady-state level. In untreated cells, degradation of (35)S-labeled ER was characterized by a slow phase followed by a more rapid decline. Without ligand, ER elimination was totally compensated by synthesis which maintained receptor homeostasis. Estradiol (E(2)) and the pure antiestrogen RU 58,668 abolished the slow phase of ER breakdown and enhanced the degradation of neosynthesized ER, producing a low ER steady-state level. By contrast, the partial antiestrogen OH-Tam was ineffective in this respect and caused ER accumulation. Regardless of the conditions, ER breakdown was abolished by proteasome inhibition (MG-132). ER ligands decreased cell capacity to bind [(3)H]E(2), even in the presence of MG-132, indicating that the regulation of ER level and E(2) binding capacity occurs through distinct mechanisms. MG-132 partially blocked the basal transcription of an ERE-dependent reporter gene and modified the ability of E(2) to induce the expression of the latter: the hormone was unable to restore the transactivation activity measured without MG-132. RU 58,668 and OH-Tam failed to enhance the inhibitory action of MG-132, suggesting that a loss of basal ER-mediated transactivation mainly affects the stimulatory effect of estrogens. Overall, our findings reveal that ER steady state level, ligand binding capacity and transactivation potency fit in a complex regulatory scheme involving distinct mechanisms, which may be dissociated from each other under various treatments.

Breast Neoplasms↗
PubMed2006

Less calcemic Vitamin D analogs enhance creatine kinase specific activity and modulate responsiveness to gonadal steroids in the vasculature.

Vitamin D receptors are widely expressed in the cardiovascular system, in which Vitamin D and its metabolites exert a variety of biological activities such as regulation of cellular proliferation and differentiation, cell calcium transients and cell energy metabolism in vitro. The latter is mediated through the control of the brain type creatine kinase specific activity (CK), which serves to provide a readily available reservoir for ATP generation under increased work-load. In the present study we undertook to assess the role of Vitamin D on energy metabolism in the rat heart and aorta in vivo by using CK, which is a key energy metabolizing enzyme and compare Vitamin D depleted and repleted animals. Vascular tissues from female or male Vitamin D-depleted rats showed 61-80% lower CK activity in the aorta (Ao) and left ventricle of the heart (Lv) than control, Vitamin D-replete rats. Moreover, neither estradiol-17beta (E2) nor dihydrotestosterone (DHT), which increases CK specific activity in Ao and Lv of intact female or male rats, respectively, were able to stimulate CK in Vitamin D-depleted rats. Treatment of intact female rats for 2 weeks or 2 months with the less-calcemic Vitamin D analogs JKF 1624F2-2 (JKF) or QW 1624F2-2 (QW) (Fig. 1), did not significantly affect CK specific activity. However, after pretreatment with these analogs, there was an up regulation of the E2-induced CK response in Ao and Lv. In intact female rats, all Vitamin D analogs also potentiated the in vivo CK response to the SERMs raloxifene (Ral) and tamoxifen (TAM) in Ao and Lv. However the inhibitory effect of Ral or TAM on E2-induced CK activity was lost after pretreatment with Vitamin D analogs. The non-calcemic analog CB 1093 (CB) induced a significant increase in estradiol receptor alpha (ERalpha) protein in both myocardial and aortic tissue from intact and from ovariectomized female rats. Collectively, these results indicate that Vitamin D analogs modulate cell energy homeostasis in vascular tissues through induction of CK and up regulation of the response and sensitivity of CK in vascular tissues to E2 and to SERMs, possibly through via an increase in ERalpha protein in female derived organs. These results corroborate our previous in vitro studies in human vascular cells and further suggest that the Vitamin D system plays an important physiological role in maintaining normal cell energy reservoir in the vasculature.

Animals↗
PubMed2003

[Reinsertion of the flexor tendon using a suture anchor: prospective study using early active motion].

INTRODUCTION: The aim of this study was to evaluate subjective and functional results of a prospective continuous series of immediate tendon-to-bone repair of the F.D.L. using a miniaturized anchor. METHOD: Seven patients have been operated by the same surgeon in emergency for a section of the FDL in zone one. Distal tendon-to-bone re-attachment has been realized using a mini-G II Mitek anchor suture. Five of the patient were male, four of them being manual workers. Only one had a work accident. According to Leddy and Packer's classification one patient had a stage 1 lesion and the six others had stage two lesions. The injured fingers showed associated lesions in four cases. Rehabilitation consisted of early active mobilization protected by a Duran-type splint. All the patients had been examined by an independent surgeon at 10 months follow-up. Mean age at that time was 32 years. RESULTS: One patient was very satisfied with his results while the six others were satisfied. Two minor complications were encountered, one of them being directly in relation to the implant. Total Active Motion (TAM) summed up to 92% of the arch of motion of the normal controlateral finger. Pinch-force reached 81% compared to that of the controlateral finger. Two patients described no pain. Mean eviction from work was 70 days. DISCUSSION: Tendon-to-bone repair of the FDL using an anchor seems to give good results on pain, TAM and on force. The only complication due to the implant did not have any functional incidence. The series of Marin Braun on 77 cases of such repairs using a barb-wire show similar results compared to the implant used in our series. However, anchor sutures have several advantages compared to a transcutaneous device: they reduce the risk of infection, of nail dystrophy and they offer a better comfort to the patient.

Adolescent↗
PubMed2005

Tissue-specific modulation of cyclooxygenase-2 (Cox-2) expression in the uterus and the v. cava by estrogens and phytoestrogens.

Cyclooxygenase 2 (Cox-2), an enzyme involved in prostaglandin production, is a key player in the development of pathologic changes, such as colorectal cancer, arteriosclerosis and thrombosis. In this study, we investigated the effects of estrogens, selective estrogen receptor modulators (SERMs), pure antiestrogens and phytoestrogens on the tissue-specific expression of Cox-2 in the uterus and the v. cava of ovariectomized female rats. Cox-2 expression could be detected in the uterine epithelium and in the endothelium of the v. cava. Cox-2 expression was time-dependently stimulated after administration of 17beta estradiol (E2) in the uterus. In the v. cava, E2 treatment resulted in a stimulated expression of the progesterone receptor (PR), a gene known to be regulated by E2, whereas Cox-2 was simultaneously down-regulated. Administration of the pure antiestrogen faslodex (Fas) had no effect on Cox-2 expression. In contrast, administration of tamoxifen (Tam) resulted in a decrease of Cox-2 expression in the v. cava but does not stimulate Cox-2 expression in the uterus. Interestingly, the same expression pattern of Cox-2 could be detected after dose-dependent administration of genistein (Gen). Here, down-regulation of Cox-2 could already be detected after administration of merely 0.5 mg/(kgBW) Gen, a dose where no effects on uterine weight were observed. In summary, our results demonstrate a reverse tissue-specific regulation of Cox-2 expression by estrogens in the v. cava and uterus indicating the existence of complex molecular mechanisms which have to be characterized in future studies. Remarkably, Tam and the phytoestrogen Gen, both share the ability to decrease the expression of Cox-2 in the v. cava without effecting its uterine expression. These observations may be of great importance with respect to potential beneficial or adverse effects of estrogens, SERMs and phytoestrogens on the cardiovascular tissue.

Animals↗
PubMed2005

ERE-independent ERalpha target genes differentially expressed in human breast tumors.

The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERalpha can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-kappaB) at their cognate sites on DNA. We previously generated a mutant form of ERalpha (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERalpha into MDA-MB231 ERalpha-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17beta-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERalpha pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERalpha responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERalpha pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERalpha target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.

Breast Neoplasms↗
PubMed2004

Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors.

Leukocytes, and macrophages in particular, are an important component of the stroma of neoplastic tissues. Tumor-associated macrophages (TAM) have the properties of a polarized M2 population and are a key component of inflammatory circuits which promote tumor growth and progression. Chemokines play a key role in the recruitment and positioning of TAM and dendritic cells in tumors and contribute to shaping their functional properties. Chemokine-recruited and positioned tumor infiltrating leukocytes are a key component of inflammatory circuits which promote tumor progression.

Chemokines↗
PubMed2004

Reproductive traits in the spur-thighed tortoise (Testudo graeca terrestris): new tools for the enhancement of reproductive success and survivorship.

The Mediterranean tortoise (Testudo graeca) is listed as "Vulnerable" on the IUCN Red List. Reproductive characteristics and means to increase offspring production were studied in T. graeca terrestris in a semi-natural environment. Courtship and mating occurred during early spring for about 4 weeks, followed by a laying season of approximately 2 months, with a second, shorter mating period in the fall. During the first mating, calcified eggs were already present in the uterus; we inferred that sperm from both mating seasons were stored in the oviduct for fertilization of eggs of the second laying cycle and of the following year. Average egg production was 3.8+/-0.3 eggs/year. Most females laid all of their eggs in a single clutch, but 18% laid in a second clutch, 11-21 days later. X-ray radiography revealed calcified eggs in the uterus about 4 weeks before oviposition. All eggs in the uterus were calcified simultaneously and were laid in a single clutch; if a second clutch developed, those eggs were also calcified simultaneously. Based on endoscopic examinations, ovaries were active throughout the entire year. Plasma progesterone concentrations in females were very low and were detected only soon after oviposition ( 440 +/-141 pg/ml). Plasma estradiol concentrations in females varied from 4.1 +/-1.5 pg/ml to 70.2 +/-29.4 pg/ml, with no clear seasonal pattern. Maintaining tortoises at a low environmental temperature (9 +/-1 degrees C versus 28 +/- 1 degrees C) reduced plasma estradiol concentrations. Giving 2mg/kg tamoxifen (TAM) increased plasma estradiol to 220 +/-33 pg/ml when treatment was given in September but not in late October, winter or spring. Treatment with TAM increased the number of eggs laid during the following laying season to 7.3 +/- 1.0 eggs/year, laid in one to three clutches. In males, plasma testosterone concentrations had a seasonal pattern with the onset of a rise in July from 2 to >4ng/ml, a continued increase to a peak of 12.8+/-5.3 ng/ml during November and a decline thereafter. Artificial incubation in sand at 29 +/-1 degrees C shortened the natural incubation time of 103+/-3.1 days to 83.5 +/- 1.3 days, increased hatching rate from 28 to 53%, and increased survival rate from 51 to 71% at 40 weeks of age. In summary, this study provides options for increasing reproductive performance, hatchability and offspring survival in captive Mediterranean tortoises, and may offer new tools for conservation of animals that are on the verge of extinction.

Animals↗
PubMed2024

Protocol to decode the role of transcriptionally active microbes in SARS-CoV-2-positive patients using an RNA-seq-based approach.

The elucidation of the role of microorganisms in human infections has been hindered by difficulties using conventional culture-based techniques. Here, we present a protocol for the investigation of transcriptionally active microbes (TAMs) using an RNA sequencing (RNA-seq)-based approach. We describe the steps for RNA isolation, viral genome sequencing, RNA-seq library preparation, and metatranscriptomic and transcriptomic analysis. This protocol permits a comprehensive evaluation of TAMs' contributions to the differential severity of infectious diseases, with a particular focus on diseases such as COVID-19. For complete details on the use and execution of this protocol, please refer to Devi et al.1.

Humans↗
PubMed2005

Luteinizing hormone, follicle stimulating hormone, and gonadotropin releasing hormone mRNA expression of Xenopus laevis in response to endocrine disrupting compounds affecting reproductive biology.

Environmental pollutants can interfere with the endocrine system of a variety of animals and are suggested to contribute to the worldwide decline of amphibians. In this study, the effects of endocrine disrupting compounds (EDC) on the hypothalamus-pituitary-gonad axis, regulating reproduction, were investigated in Xenopus laevis by determining their potential impact on gene expression of gonadotropin releasing hormone (GnRH), luteinizing hormone beta-subunit (LHbeta) and follicle-stimulating hormone beta-subunit (FSHbeta) in brain and pituitary using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). One environmental sample and four model compounds, ethinylestradiol (EE2), tamoxifen (TAM), methyldihydrotestosterone (MDHT), and flutamide (FLU), corresponding to (anti)estrogenic and (anti)androgenic modes of action were used at 10(-8)M during a four weeks exposure of adults of both sexes. In general, males had a higher LHbeta mRNA level compared to females, while the mRNA expression of FSHbeta and GnRH did not differ between both sexes. EE2 and MDHT treatment decreased LHbeta mRNA expression in the brain of male X. laevis, while only EE2 but not MDHT reduced LHbeta mRNA in females indicating classical negative feed-back mechanisms on hypophyseal gonadotropin expression. TAM increased LHbeta mRNA and FSHbeta mRNA expression in female X. laevis while none of the other treatments showed an effect on FSHbeta mRNA expression. GnRH expression was not changed by any treatment and exposure of X. laevis to Lambro river water had no significant effect on any of the genes examined. It is reported for the first time in amphibians that gonadotropin mRNA expression is differentially regulated by (anti)estrogenic and (anti)androgenic EDC and that gender-specific patterns of gene expression exist.

Animals↗
PubMed1986

New evidence that the antiestrogen binding site may be a novel growth-promoting histamine receptor (?H3) which mediates the antiestrogenic and antiproliferative effects of tamoxifen.

Using as a probe [3H]-DPPE (N,N-diethyl-2-[(4-phenylmethyl)phenoxy]ethanamine HCl), a novel compound selective for the antiestrogen binding site (AEBS), new evidence is presented that this site could be a growth-promoting histamine receptor of a type not previously described (?H3). In the rat uterus, DPPE alone at a concentration of 4 mg/kg acts as an estrogen antagonist, unlike TAM alone which is a partial estrogen agonist. In the presence of exogenous estradiol, both TAM and DPPE are partial antagonists. This suggests that the "antiestrogenic" effects of tamoxifen are mediated through AEBS/?H3 while the estrogenic effects are mediated through ER.

Animals↗
PubMed1997

Inhibition of phorbol ester-stimulated phospholipase D activity by chronic tamoxifen treatment in breast cancer cells.

We have shown that in an estrogen receptor-negative multidrug-resistant subline of MCF-7 human breast carcinoma cells longer-term (24 h), but not shorter-term (30 min), treatments with clinically relevant (2-5 microM) concentrations of tamoxifen (TAM) inhibited phorbol ester-stimulated phospholipase D (PLD) activity by 50-80%. TAM caused these inhibitory effects without inducing membrane translocation or down-regulation of protein kinase C-alpha, the major mediator of phorbol ester effects on PLD activation. The results raise the possibility that prolonged inhibition of the protein kinase C-alpha-regulated PLD system may contribute to the cytotoxic effects of tamoxifen in estrogen receptor-negative breast cancer cells.

3T3 Cells↗
PubMed1997

BIT, an immune antigen receptor-like molecule in the brain.

We previously found a brain-specific glycoprotein in the rat brain. It postnatally increases and is rich in the mature brain. We cloned cDNA of this protein. It is composed of a signal peptide, a V-type immunoglobulin domain, two C1-type immunoglobulin domains, a transmembrane segment and a cytoplasmic region containing two tyrosine-based activation motifs (TAM) that are variants of the antigen receptor signaling motifs. The overall structure is similar to those of immune antigen receptors. This molecule, BIT (brain immunoglobulin-like molecule with TAMs), is a major endogenous substrates of brain tyrosine kinases in vitro. Cerebral cortical neurons could extend their neurites on BIT-coated substrate and anti-BIT monoclonal antibody specifically inhibited the effect. These findings and our recent study concerning BIT signal transduction mechanism suggest that BIT, an immune antigen receptor-like molecule of the brain, functions as a membrane signaling molecule that may participate in cell-cell interaction.

Amino Acid Sequence↗
PubMed1987

Tamoxifen citrate therapy in male infertility.

A prospective, randomized, double-blind study with crossover, using tamoxifen (TAM) (Nolvadex, ici Pharma, Missisauga, Canada) 20 mg/day and placebo (p) for 6 months each, was conducted in 16 infertile men with idiopathic oligozoospermia. Baseline sperm count was 17.092 +/- 3.09 (10(6)/ml). Hormonal profile was performed and included follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), prolactin (PRL), thyroid-stimulating hormone (TSH), and luteinizing hormone-releasing hormone (LH-RH) stimulation tests. The sperm analysis and hormonal profile were repeated at 6 and 12 months of the study. A sperm penetration assay (SPA) was performed on zona-free hamster egg. Compared with the placebo group, the TAM group showed a significant increase in plasma FSH, LH, E2, and T levels (P less than 0.001), but not in PRL and TSH levels. However, LH-RH stimulation tests and SPA were found to be comparable in the two treatment groups, and there was no significant effect on sperm analysis. Tamoxifen appeared to be no more effective than the placebo in the treatment of idiopathic oligozoospermia.

Adult↗
PubMed2003

Decrease of estrogen receptor expression and associated ERE-dependent transcription in MCF-7 breast cancer cells after oligomycin treatment.

Oligomycin at 0.01 microM produces very rapid decrease of [3H]estradiol (E2)-binding capacity in MCF-7 cells maintained in culture in glucose- and serum-free medium. Loss of binding capacity was associated with elimination of the estrogen receptor (ER) as well as a decrease of basal expression of ERE-luciferase reporter gene. These effects were not due to major cell death as shown by MTT assay. Hence, the inhibition of ATP synthesis produced by oligomycin seems to influence ER turnover, resulting in very rapid loss of receptor. Withdrawal of oligomycin and maintenance of glucose in the medium led to only a partial reappearance of ER and failed to restore optimal ERE-dependent transcription. Oligomycin significantly down-regulated progesterone receptor (PR) level and partially abrogated E2-induced PR up-regulation, indicating that this drug also affects other nuclear receptors. Treatment of cytosol from MCF-7 cells with acid and alkaline phosphatases decreased [3H]E2-binding capacity, indicating the requirement of ER phosphorylation for optimal hormone binding. On the other hand, oligomycin-induced ER loss was partly compensated by E2 and partial anti-estrogens (AEs; 4-OH-TAM or RU 39 411); i.e. oligomycin failed to improve the E2-induced ER down-regulation and very weakly suppressed partial AE-induced receptor up-regulation. The known ability of these ligands to stabilize ER in the cell nucleus before regulating ER level may explain this phenomenon since such antagonism was not recorded with pure AE RU 58 668, which is known to impede nuclear translocation of the receptor. Interestingly, ligands able to down-regulate ER (i.e. E2 or RU 58 668) increased ER phosphorylation while 4-OH-TAM which up-regulate the receptor had little effect in this regard. Oligomycin failed to strongly affect such phosphorylation enhancements while it produced a weak decrease of basal phosphorylation level. Hence, phosphorylations/dephosphorylations of specific sites on ER and/or co-regulators seem to govern its turnover.

Binding Sites↗
PubMed2001

Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats.

Previous work from this laboratory has revealed that female rats acquired cocaine self-administration at a faster rate than male rats and that a greater percentage of females acquired self-administration [Psychopharmacology 144 (1999) 77.]. It has been suggested that sex differences in stimulant self-administration may be related to ovarian hormones, particularly estrogen. To investigate this possibility, we compared four groups (n = 10) of female rats: ovariectomized (OVX) treated with either estradiol benzoate (EB) or vehicle (VEH), and sham-operated intact (SH) females treated with either the antiestrogen tamoxifen (TAM) or VEH. An autoshaping procedure was used to train rats to lever press for intravenous infusions of cocaine (0.2 mg/kg). The criterion for cocaine acquisition was a mean of 100 self-administered infusions over five consecutive 6-h sessions. Results revealed that 70% of the OVX + EB group and 80% of the SH + VEH group acquired self-administration, while only 30% of the OVX + VEH group and 50% of the SH + TAM group met the acquisition criterion. Rats that had estrogen chemically or surgically blocked exhibited significantly less responding for cocaine over the acquisition testing period, and fewer of these rats met the acquisition criterion compared to intact rats and to OVX rats with estrogen (EB) replacement. The percentages for females with estrogen (70% and 80%) vs. those without (OVX, 30%) were similar to those reported for intact females (70%) and males (30%) in the previous study [Psychopharmacology (2000)]. Taken together, these results suggest that estrogen is a key factor influencing drug-seeking behavior in female rats, and it may underlie sex differences in drug-reinforced responding.

Animals↗
PubMed1998

Myelodysplastic syndrome after regression of transient abnormal myelopoiesis in a Down syndrome infant: different clonal origin?

A boy with Down syndrome who developed myelodysplastic syndrome after regression of transient abnormal myelopoiesis (TAM) is described. His blast cells in TAM had other chromosome abnormalities in addition to trisomy 21;50,XY,+21c,+12,+14,+21. Serial chromosome analysis in follow-up showed abnormal clones involving monosomy 7. Myelodysplastic syndrome was diagnosed. Because two clones had different karyotypes, they might have derived from different clones.

Chromosome Aberrations↗
PubMed2002

Two antiestrogens affect differently chromatin remodeling of trefoil factor 1 (pS2) gene and the fate of estrogen receptor in MCF7 cells.

We show here that the two antagonists ICI 182 780, a pure estrogen antagonist, and 4-hydroxy-tamoxifen, a selective estrogen receptor modulator (SERM) have distinct effects on TFF1 (formerly pS2) gene chromatin structure and transcription. Indeed, ICI 182 780 decreased both the intensity of the hormone-dependent DNase I hypersensitive site pS2 HS-1 and transcription of the pS2 gene whereas 4-hydroxy-tamoxifen (OH-Tam) increased the intensity of pS2-HS1 and had no effect on pS2 gene transcription. Interestingly, these differential effects are associated with different fates of ERalpha following the two treatments: The ERalpha-OH-Tam complex was retained in the nucleus more efficiently than the ERalpha-estradiol complex. In contrast, ICI 182 780 provoked a rapid relocation of ERalpha complex to an insoluble nuclear fraction, followed by its degradation. Taken together, these data suggest that regulating the amount of ERalpha in the nucleus is a major way of action of estrogen antagonists with respect to chromatin remodeling and transcriptional control.

Blotting, Western↗