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At least 415 records · Page 23Linked to original sources
PubMed2004

HMR 3339, a novel selective estrogen receptor modulator, reduces total cholesterol, low-density lipoprotein cholesterol, and homocysteine in healthy postmenopausal women.

OBJECTIVE: To investigate the short-term effects of HMR 3339 in comparison with raloxifene and placebo on cardiovascular risk factors. DESIGN: A multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. SETTING: Gynecologic outpatient department. PATIENT(S): One hundred eighteen healthy nonhysterectomized postmenopausal women. INTERVENTION(S): Participants received daily placebo (n = 22), 2.5 mg of HMR 3339 (n = 25), 10 mg of HMR 3339 (n = 24), 50 mg of HMR 3339 (n = 24), or 60 mg of raloxifene (n = 23) for 12 weeks followed by a 2-week washout period. MAIN OUTCOME MEASURE(S): Blood concentrations of lipids measured at baseline, and after 2, 4, 8, 12, and 14 weeks, and of lipoprotein(a), homocysteine, and endothelin-1 measured at baseline, and after 4 and 12 weeks. RESULT(S): After 12 weeks of treatment with HMR 3339, compared with placebo, serum total cholesterol was reduced (10 mg of HMR 3339: -9.7%; 50 mg of HMR 3339: -15.2%), low-density lipoprotein (LDL)-cholesterol (10 mg of HMR 3339: -10.8%; 50 mg of HMR 3339: -24.2%) and plasma homocysteine concentrations (2.5 mg of HMR 3339: -3.9%; 10 mg of HMR 3339: -10.8%; 50 mg of HMR 3339: -13.8%), suggesting a dose-dependent effect of HMR 3339. These effects were already apparent after 2 weeks of treatment for total cholesterol and LDL-cholesterol, and after 4 weeks of treatment for homocysteine. After 12 weeks, raloxifene, compared with placebo, significantly decreased total cholesterol (-10.5%), LDL-cholesterol (-15.0%), and triglycerides (-16.9%), but not homocysteine. High-density lipoprotein-cholesterol, lipoprotein(a), and endothelin-1 showed no significant changes in any of the active treatment groups. CONCLUSION(S): HMR 3339 reduces total cholesterol, LDL-cholesterol, and homocysteine concentrations in postmenopausal women.

Anticholesteremic Agents↗
PubMed2004

In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague-Dawley rats by ormeloxifene, a selective estrogen receptor modulator.

Antiosteoporotic activity of ormeloxifene, a multifunctional SERM, using inhibition in parathyroid hormone (PTH) induced resorption of 45Ca from prelabeled chick and rat fetal limb bones in chase cultures and modulation of certain biochemical markers of bone turnover and bone mineral density (BMD) in ovariectomized adult female rats, was investigated. Ormeloxifene concentration-dependently inhibited PTH-induced resorption of 45Ca from chick fetal femora with treated/control (T/C) ratio of 0.71, 0.32 and 0.20 at 50, 100 and 200 microM concentration, in comparison to 0.49, 0.53 and 0.95 in case of CDRI-85/287 (a pure antiestrogen), tamoxifen and ethynylestradiol (100 microM), respectively. Using rat fetal limb bones, ormeloxifene (100 microM) exhibited T/C ratio of 0.67, in comparison to 1.43 with PTH alone. Heat-killed bones exhibited negligible resorption (2.9%; T/C: 0.098) in response to PTH. In adult female rats, ormeloxifene (1.25 and 12.5 mg/kg per day) inhibited ovariectomy-induced increase in serum total and bone-specific alkaline phosphatase and osteocalcin and urine calcium/creatinine ratio to almost intact control level. Ovariectomy was accompanied by marked decrease in bone mineral density of isolated femur and tibia, being maximum in femur neck (28.3%; P < 0.01) and midshaft (23.7%; P < 0.01), but only marginal (6.7%; P > 0.05) in region proximal to tibio-fibular separation point. Decrease in BMD based on T-/Z-score, too, was >2.5 S.D. than mean value of normal young adult/age-matched females. This was prevented by ormeloxifene and the effect, though apparently more in females supplemented with higher dose of ormeloxifene, was not always significantly different and clear dose-response was not evident until BMD data was evaluated on T-/Z-score basis. The analysis also demonstrated much higher threshold level of tibia than femur and more so for their mid-shafts. Increase in BMD of isolated bones was also observed in ormeloxifene-treated intact females, without significantly altering biochemical markers of bone turnover or uterine weight. Findings suggest potential of ormeloxifene in management of post-menopausal osteoporosis and beneficial effect on BMD in women taking this SERM for contraception or any hormone-related clinical disorder.

Animals↗
PubMed1999

[Selective estrogen-receptor modulators (SERM's) in postmenopausal women].

Selective oestrogen receptor modulators (SERMs) constitute a group of new drugs which mimic oestrogen in some organs and tissues but have an oestrogen antagonistic mode of action in other tissues. In postmenopausal women these compounds have a favourable effect on lipoprotein cholesterol levels in the blood and bone mineral density, thereby reducing fracture risk, especially in the vertebral column. In contrast to oestrogen therapy SERMs reduce the risk of mammary carcinoma. Currently tamoxifen and raloxifene are the best known SERMs. Tamoxifen increases endometrial hyperplasia and the risk of endometrial carcinoma. Raloxifene inhibits uterine tissue proliferation and does not appear to influence the endometrium directly. Raloxifene appears to be finding a place for itself in the treatment and prevention of osteoporosis in postmenopausal women. At this moment it is not yet possible to foresee what the impact of SERMs will be in the treatment and prevention of cardiovascular diseases and breast cancer.

Aged↗
PubMed2006

Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators?

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.

Breast Neoplasms↗
PubMed2001

Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone. The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery. Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2-3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic. Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue--culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.

Adaptation, Physiological↗
PubMedDate not supplied

Protein kinase C modulates estrogen receptors in differentiated osteoblastic cells in vitro.

Several reports have shown an interaction between the estrogen receptor (ER) and the protein kinase C (PKC) intracellular pathways. Data from our laboratory showed that PKC activation can modulate ER levels and responsiveness in estrogen target tissues such as uterus and bone. In particular, ROS.SMER #14 osteoblastic cells, stably transfected with the mouse ER, undergo specific morphological changes in vitro. ROS.SMER #14 cells at post-confluence express a differentiated phenotype and become unresponsive to estrogenic stimulation. Interestingly, ER mRNA and protein levels were not modified by post-confluence, but ER binding sites/cell (2500-3000/cell at subconfluence) were undetectable. Moreover, PKC activity was significantly increased in post-confluent cells. Inhibition of PKC by H7 or staurosporin (PKC inhibitors) or down-regulation by long-term treatment with 12-O-tetradecanoylphorbol-13-acetate enchanced ER binding capacity in a dose-dependent manner. Since the PKC family includes several different isoforms that play different roles in cell homeostasis, we evaluated whether specific isoenzymes were involved in this event. To address this question, Western blotting analysis was performed on both sub- and post-confluent ROS.SMER #14 cells using antibodies against different PKC isoforms. In conclusion, our preliminary data indicate that estrogen responsiveness of osteoblastic cells can be highly regulated by PKC. Finally, these data suggest that this intracellular interaction might play an important role in modulating hormonal and pharmacological responsiveness of bone tissue.

Animals↗
PubMed2006

Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats.

Estradiol (E(2)) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the beta isoform of estrogen receptor (ER) are important for E(2)'s effects for anxiety and/or depressive behavior. Whether ERbeta in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERbeta in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERbeta than ERalpha to the hippocampus, but not a control region/missed sites (i.e. the ventral tegmental area), should decrease anxiety and depressive behavior, compared to vehicle and that ERalpha-specific SERMs should not have the same effect. To investigate this, ovariectomized (ovx) rats were surgically-implanted with guide cannulae aimed at the hippocampus (target site) or ventral tegmental area (control site). Rats were administered vehicle, or 17beta-E(2) (equal affinity for ERalpha and ERbeta), SERMs with greater affinity for ERalpha vs. ERbeta (17alpha-E(2) or propyl pyrazole triol), or SERMs with greater affinity for ERbeta vs. ERalpha (coumestrol or diarylpropionitrile) to these sites (2 microg/microl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERbeta-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17beta-E(2) or ERbeta SERMs entered more central squares in an open field, spent more time on the open arms of the plus maze, and spent less time immobile compared to rats administered vehicle. Administration of ERalpha-specific SERMs produced similar effects as vehicle administration. Thus, E(2)'s anti-anxiety and anti-depressive effects may involve ERbeta in the hippocampus.

Animals↗
PubMedDate not supplied

Estradiol and a selective estrogen receptor modulator affect steroid hormone receptor messenger RNA levels and turnover in explant cultures of sheep endometrium.

Estrogens upregulate estrogen receptor (ER) and progesterone receptor (PR) gene expression in endometrium immediately before ovulation to prepare it for nurturing embryos. Most in vitro model systems have lost the ability to upregulate expression of the ER gene in response to estradiol (E2) or the ability to express the ER gene at all. Here, we used explant cultures from control and E2-treated ewes and assessed expression of four genes (ER, PR, glyceraldehyde 3-phosphate dehydrogenase [GAPDH], and cyclophilin [CYC] genes) that are upregulated by E2 in vivo on Northern blots. In cultures from control and E2-treated ewes, ER and PR messenger ribonucleic acid (mRNA) levels dropped significantly during 24 h of culture in the absence of E2. Glyceraldehyde 3-phosphate dehydrogenase mRNA levels increased 300% in explants from control ewes to match the higher levels in the endometrium of the E2-treated ewe (in vivo and in explant culture). The only effect of E2 in the explant cultures was to prevent the decrease in PR mRNA. The new selective ER modulator, EM-800 (EM), decreased ER and PR mRNA levels in explants from control ewes but upregulated GAPDH and CYC mRNA levels. The EM treatment in vitro mimicked that of E2 by increasing the half-life of ER mRNA in endometrial explants. These data illustrate distinct, gene-specific effects of the explant culture process, E2, and EM on the expression of endometrial genes.

Animals↗
PubMed2001

Investigations of new lead structures for the design of selective estrogen receptor modulators.

Heterocyclic derivatives of (R,S)/(S,R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (L1) were synthesized and tested for estrogen receptor binding. The selection of the heterocycles was based on theoretical consideration. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 2, (4R,5S)/(4S,5R)-4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline 3, and 4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)imidazole 4 possess a spatial structure with neighboring aromatic rings as is realized in hormonally active [1,2-diphenylethylenediamine]platinum(II) complexes. The 1,2-diphenylethane pharmacophor, however, cannot adapt an antiperiplanar conformation to interact with the estrogen receptor (ER) comparable to synthetic (e.g., diethylstilbestrol (DES)) or steroidal (e.g., estradiol (E2)) estrogens. Due to the different spatial structures, the heterocycles cause only a marginal displacement of E2 from its binding site (relative binding affinity (RBA) < 0.1%). Nevertheless, unequivocally ER mediated gene activation was verified on the MCF-7-2a cell line. Imidazoline 3 as the most active compound reached the maximum effect of E2 (100% activation) in a concentration of 5 x 10(-7) M, while piperazine 2 and imidazole 4 activate luciferase expression only in a small but significant amount of 20% and 27%, respectively. We therefore assigned these heterocyclic compounds to a second class of hormones (type-II-estrogens), which are attached at the ER at different amino acids than DES or E2 (type-I-estrogens).

Binding, Competitive↗
PubMed2005

Anti-inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells.

OBJECTIVE: Our aim was to study how different SERMs modulate the inflammatory responses induced by lipopolysaccharide (LPS) or unmethylated CpG-oligonucleotides in mouse and rat microglial cells. MATERIALS AND METHODS: Inflammatory responses of mouse N9 microglial cells and rat primary hippocampal microglia to lipopolysaccharide (LPS) exposure were recorded by the secretion of nitric oxide (NO) and cytokine IL-6 in two models where SERM was added either 24 h before LPS addition or simultaneously or even after the LPS exposure. The responses of 17beta-estradiol, tamoxifen, raloxifene and ICI 182.780 were compared. Responses were recorded by ELISA, Northern and EMSA assays. RESULTS: SERMs but not 17beta-estradiol induced a significant, concentration-dependent anti-inflammatory response both in rat primary microglial cells and in mouse N9 microglial cells. The response was observed both in NO and IL-6 secretion as well as in total IL-6 mRNA expression. We have recently observed that histone deacetylase (HDAC) inhibitors can potentiate the LPS-induced inflammatory response. Raloxifene and tamoxifen inhibited the potentiation of LPS response induced by trichostatin A, an HDAC inhibitor, in N9 microglia. A SERM-induced anti-inflammatory response was observed in acute models where SERM was added simultaneously or even up to 6 h later than LPS exposure. In contrast, the pretreatment of N9 microglia with tamoxifen or raloxifene for 30 h before LPS exposure did not provide any protection against the LPS response. We also observed that the raloxifene-induced protection in N9 microglia was connected to a decline of LPS-induced DNA binding activity of AP-1 but not that of NF-kappaB transcription factors. CONCLUSIONS: Our results show that tamoxifen, raloxifene and ICI 182.780 induce an anti-inflammatory response in acute models of mouse and rat microglial cells. It seems that this response is not estrogen receptor-mediated but, probably, is attributable to some SERM-induced modulation of LPS-activated pro-inflammatory signalling cascades.

Animals↗
PubMed1998

Estrogens and atherosclerosis: phytoestrogens and selective estrogen receptor modulators.

The development of atherosclerosis in animal models and the incidence of coronary heart disease in postmenopausal women are markedly reduced by estrogen treatment. Estrogen have acute beneficial effects on vascular reactivity and longer-term effects on critical steps in the pathogenesis of atherosclerosis. Phytoestrogens present in soybeans and other plant products are weak estrogens but appear to have potent beneficial effects on the arterial wall. The phytoestrogens have certain similarities to 'designer hormones' which are being developed to retain their beneficial effects on the cardiovascular system and the skeleton without having cancer promoting effects on the breast and endometrium.

Animals↗
PubMed1999

Phytoestrogens: the "natural" selective estrogen receptor modulators?

Phytoestrogens are diphenolic compounds that are present in several plants eaten by human beings. Soybeans and flaxseed are particularly abundant source of phytoestrogens. When ingested in relatively large amounts, phytoestrogens have been shown to have significant estrogen agonists/antagonists effects in animals and humans. There is epidemiological, laboratory and clinical evidence which indicates that phytoestrogens, like certain selective estrogen receptor mudulators, have an antiproliferative effect on the breast, and positive effects on the lipoprotein profile and bone density. They might also improve some of the climacteric symptoms. This evidence is critically reviewed, and the possible benefit of dietary intervention with phytoestrogen-rich food for woman's health is discussed.

Breast Neoplasms↗
PubMed2002

Signaling through estrogen receptors modulates telomerase activity in human prostate cancer.

Sex steroid hormone receptors play a central role in all stages of prostate cancer. Here, we tested whether estrogen receptor (ER) signaling contributes to telomerase activation, an early event in prostate tumorigenesis. Following 17beta-estradiol (E(2)) treatment, both mRNA encoding the catalytic subunit of human telomerase (hTERT) and telomerase activity were promptly induced in human prostate normal epithelial cells, fresh explants from benign prostate hyperplasia, and prostate cancer explants and cell lines. Reporter expression studies and in vivo chromatin immunoprecipitation assays revealed E(2)-dependent hTERT promoter induction and showed that both ERalpha and ERbeta bound this sequence. Crucially, addition of the anti-estrogen 4-hydroxytamoxifen caused a differential recruitment in vivo of ERalpha and ERbeta onto the hTERT promoter and inhibited telomerase activity. Treatment with the aromatase inhibitor letrozole, which prevented testosterone-mediated interaction between ER and the hTERT estrogen response element, resulted in a negative regulation of telomerase activity. Thus, intracellular conversion of androgens to estrogens may contribute to the etiopathogenesis of prostate cancer. Given the present evidence for direct control of hTERT gene expression and telomerase activity in the prostate by the ER, we suggest that this transcriptional regulator represents a possible therapeutic target in prostate cancer.

Aromatase Inhibitors↗
PubMed2002

Regulation of GRIP1 and CBP Coactivator activity by Rho GDI modulates estrogen receptor transcriptional enhancement.

Estrogen receptor alpha (ER) coordinates gene expression with cellular physiology in part by controlling receptor- cofactor interactions in response to extracellular signals. We have previously shown that the Rho signaling pathway modulates ER transcriptional activation. We now demonstrate that Rho GDI-dependent increase in ER transactivation is dependent on the ER AF-2 coactivator binding site, prompting us to examine regulation of receptor coactivators by Rho GDI. Indeed, Rho GDI cooperates with GRIP1 to increase ER ligand-independent and ligand-dependent transactivation and also enhances GRIP1 transcriptional activity when GRIP1 is tethered to DNA. The GRIP1 activation domain 1 (AD1), which binds CBP/p300, is necessary for Rho GDI to modulate GRIP1 activity. Using E1A to inhibit the endogenous CBP/p300 and a Gal4-CBP fusion protein to assay CBP activity, we find that the effect of Rho GDI on ER transactivation is CBP/p300-dependent. Importantly, the ability of CBP/p300 to transduce the Rho GDI signal to ER occurs through both GRIP1-dependent and -independent pathways. These data suggest a complex interplay between ER transcriptional activation and the Rho signaling pathways through modulation of receptor cofactors, which may have evolved to coordinate receptor-dependent gene expression with Rho-regulated events, such as cell migration. We speculate that dysregulation of the Rho-ER axis may participate in cancer progression.

Animals↗
PubMed2005

S-palmitoylation modulates estrogen receptor alpha localization and functions.

17beta-Estradiol (E2) acts as a chemical messenger in target tissues inducing both slow nuclear and rapid extra-nuclear responses. E2 binds to its cognate nuclear receptors (ER) resulting in the activation of target gene transcription in the nucleus. In addition to these genomic effects, E2 modulates cell functions through rapid non-genomic actions. Stimulation of G-proteins, Ca(2+) influx, inositol phosphate generation as well as phospholipase C, ERK/MAPK, and PI3K/AKT activation all occur within seconds to minutes after E2 binding to a small population of ERalpha located at the plasma membrane. The great impact of these rapid signals on cell physiology renders central the knowledge of the structural bases and mechanisms that mediate extra-nuclear signaling by E2. Several laboratories, including our own, have recently elucidated the structural requirements for localization and function of plasma membrane ERalpha. This review summarizes the molecular mechanisms of E2-induced rapid non-genomic actions relevant for cell functions, highlighting the role of lipid modification (i.e., palmitoylation) in the ERalpha localization to and residence at the plasma membrane.

Animals↗