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PubMed1982

Serotonin receptor modulation by estrogen in discrete brain nuclei.

The effect of estradiol on serotonin (5HT1) receptors of ovariectomized female rats was studied in discrete brain nuclei by a micro-binding assay and quantitative autoradiography. The two methods show similar distribution of the 5HT1 receptor and estradiol significantly increases the density of receptors in the preoptic area, anterior hypothalamus, lateral septum and arcuate-median eminence. The increase in 5HT1 receptors in these particular nuclei may be related to estrogen control of ovulation and/or other estrogen-mediated central phenomena.

Animals↗
PubMed2004

Mechanisms for altered reproductive function in female rats following neonatal administration of raloxifene.

OBJECTIVE: Raloxifene is a non-steroidal selective estrogen receptor modulator (SERM) that mimics estrogenic activity on bone density and blood lipid concentration without uterotropic actions. Previous data from our laboratory indicated that, as is the case for estrogen, neonatal administration of raloxifene disturbed normal differentiation of the hypothalamic circuitries governing the gonadotropic axis. In contrast, raloxifene did not act in the same way as estrogen does on the neuronal systems controlling sexual receptivity in the female rat. At present, however, the mechanisms for these organizing effects of raloxifene are not completely elucidated. DESIGN AND METHODS: To analyze this phenomenon, female rats were injected daily with raloxifene (50, 100, 250 or 500 microg/rat per day) between days 1 and 5 of age. On day 23, hypothalamic gonadotropin-releasing hormone (LHRH) mRNA expression was assessed, and pituitary and plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured in basal and LHRH-stimulated conditions. In addition, LH and FSH responses to ovariectomy were evaluated in raloxifene-treated females. Finally, we monitored the ability of neonatal administration of a potent LHRH agonist ([d-Ala(6),d-Gly(10)]-LHRH ethylamide; 0.01 microg/kg per 12 h on days 1-5) to counteract the effects of raloxifene. RESULTS: Our analyses demonstrated that prepubertal rats (23-day-old females) treated neonatally with raloxifene showed decreased hypothalamic LHRH mRNA expression levels, reduced pituitary content of LH and FSH, reduced basal and LHRH-stimulated LH secretion in vivo and in vitro, and decreased response to ovariectomy. In addition, adult females treated neonatally with raloxifene showed anovulation and reduced serum LH levels; these effects were not prevented by the simultaneous administration of a LHRH agonist. CONCLUSION: In conclusion, our data demonstrate that neonatal administration of raloxifene can disrupt the programming of hypothalamic-pituitary-ovarian axis function. Reduced LH secretion, under basal and LHRH-stimulated conditions and after ovariectomy, is probably related to decreased LHRH expression, reduced pituitary LH content and/or decreased pituitary responsiveness to hypothalamic LHRH.

Animals↗
PubMed2003

Synthesis and estrogen receptor binding affinities of 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-ones containing a basic side chain.

Two isoflavones containing a sulfur or oxygen hinge with an amine-bearing side chain have been designed and synthesized as potential selective estrogen receptor modulators. The target compounds exhibited low affinities for estrogen receptors (ERs), and binding affinity data indicate that oxygen hinge is more favorable than sulfur for binding. These compounds also displayed selectivity for ERalpha over ERbeta.

Benzopyrans↗
PubMed2001

What would be the properties of an ideal SERM?

Selective estrogen receptor modulators (SERMs) are drugs that bind to the estrogen receptor (ER); in some tissues they act like estrogen (agonists), while in other tissues they oppose the action of estrogen (antagonists). The SERM tamoxifen acts as an estrogen antagonist in the breast in that it prevents and treats breast cancer, but it acts as an estrogen agonist in the endometrium, where it can induce cancer. Estrogen, and to a lesser extent SERMs, are effective in preventing and treating osteoporosis. Contrary to the prevalent hypothesis that estrogen provides benefit to women with regard to secondary prevention of coronary heart disease (CHD), randomized clinical trials have demonstrated that estrogen is associated with an increased risk of CHD in this population of women. Conflicting results have been reported on the effect of estrogens on cognitive function. The latest and largest randomized clinical trials have demonstrated a beneficial role in short-term memory in nondemented women, in contrast to the absence of such benefit in improving symptoms in women with Alzheimer's disease. Although estrogens have been used successfully to treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and raloxifene actually induce or increase hot flashes. Data on the beneficial and adverse effects of estrogen and SERMs are reported along with an elaboration of the constellation of properties that would characterize an ideal SERM working through the ER.

Breast Neoplasms↗
PubMed2005

Estrogen modulates endothelial and neuronal nitric oxide synthase expression via an estrogen receptor beta-dependent mechanism in hypothalamic slice cultures.

Although it is evident that estrogen has important physiological effects in the brain, the signaling mechanisms mediating these effects remain unclear. We recently showed that estrogen mediates attenuated blood pressure responses to psychological stress in ovariectomized female rats through brain nitric oxide (NO). An area likely to mediate these effects is the hypothalamic paraventricular nucleus (PVN), because here NO exerts inhibitory effects on autonomic output to the periphery. Because little is known about how estrogen acts on the NO system in the PVN, our aim was to study the effects of estrogen on the NO system in the PVN of hypothalamic slices cultures. We show that 17beta-estradiol (E2; 1 nm) increases endothelial NO synthase (eNOS) protein expression and decreases the numbers of neuronal NOS (nNOS)-positive neurons in the PVN after 8 and 24 h, respectively. Using the nonselective estrogen receptor (ER) antagonist, ICI 182,780 (10 nm), we determined that E2-induced changes in NOS expression in the PVN are ER dependent. Using the ERbeta agonist, genistein (0.1 microm), we determined that activation of ERbeta induces increased eNOS expression and a decreased number of nNOS-positive neurons. We used the selective ERalpha agonist, propyl-pyrazole-triol (10 nm), and antagonist, methyl-piperidino-pyrazole (1 microm), to exclude the possibility that ERalpha is involved in the E2-induced increase in eNOS and nNOS in the PVN. These results demonstrate that E2 induces changes in NOS expression in the PVN and that these effects are ERbeta dependent.

Animals↗
PubMed2006

Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure.

Over 6 billion pounds per year of the estrogenic monomer bisphenol A (BPA) are used to manufacture polycarbonate plastic products, in resins lining metal cans, in dental sealants, and in blends with other types of plastic products. The ester bond linking BPA molecules in polycarbonate and resins undergoes hydrolysis, resulting in the release of free BPA into food, beverages, and the environment, and numerous monitoring studies now show almost ubiquitous human exposure to biologically active levels of this chemical. BPA exerts estrogenic effects through the classical nuclear estrogen receptors, and BPA acts as a selective estrogen receptor modulator. However, BPA also initiates rapid responses via estrogen receptors presumably associated with the plasma membrane. Similar to estradiol, BPA causes changes in some cell functions at concentrations between 1 pM and 1 nM, and the mean and median range of unconjugated BPA measured by multiple techniques in human pregnant maternal, fetal, and adult blood and other tissues exceeds these levels. In contrast to these published findings, BPA manufacturers persist in describing BPA as a weak estrogen and insist there is little concern with human exposure levels. Our concern with human exposure to BPA derives from 1) identification of molecular mechanisms mediating effects in human and animal tissues at very low doses, 2) in vivo effects in experimental animals caused by low doses within the range of human exposure, and 3) widespread human exposure to levels of BPA that cause adverse effects in animals.

Animals↗
PubMed2006

[Molecular mechanism of tissue-specific actions of SERM].

Selective estrogen receptor modulator (SERM) is designated as synthetic ligands for estrogen receptors (ERs), exhibiting tissue-specific agonisitic/antagonisitic activities. Among SERM, raloxifen is a most clinically successful as an anti-oseteoporotic agent. Such tissue-specific actions of SERM are presumed to mediate through unusual structure alteration of liganded ERs coupled with co-regulator recruitments.

Bone Density Conservation Agents↗
PubMed2004

p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells.

Steroid hormones bind to their receptors and trans-activate target genes. Rapid non-genomic action of steroid hormones has been proposed in addition to the one at the genomic level. Estrogen has been described to activate c-Src kinase and this activation has been shown to be responsible for estrogen-dependent mitogenicity. A major substrate of c-Src kinase activity is the cytoskeletal protein p130Cas, originally identified in v-Src-transformed cells. We show that in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas rapidly and transiently associates with the estrogen receptor alpha in a multi-molecular complex containing the c-Src kinase and the p85 subunit of PI 3-kinase. Association of p130Cas with the estrogen receptor alpha occurs within 3 minutes of estrogen treatment and is dependent on c-Src kinase activation. Transient overexpression of p130Cas in T47D cells increases estrogen-dependent Src kinase and Erk1/2 MAPKs activities and accelerates their kinetics of stimulation. A similar effect was detected on estrogen-dependent cyclin D1 expression, suggesting a role for p130Cas in regulating estrogen-dependent cell cycle progression. Double-stranded small RNA interference (siRNA) by silencing endogenous p130Cas protein, was sufficient to inhibit estrogen-dependent Erk1/2 MAPKs activity and cyclin D1 induction, demonstrating the requirement of p130Cas in such events. Therefore, our data show that the adaptor protein p130Cas associates with the estrogen receptor transducing complex, regulating estrogen-dependent activation of c-Src kinase and downstream signaling pathways.

Breast Neoplasms↗
PubMed2005

Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin.

OBJECTIVES: In different tissues, estrogens, selective estrogen receptor modulators (SERMs), and anti-estrogens exert different biologic activities. For the endometrium, estradiol and tamoxifen induce proliferation, and because of this, tamoxifen treatment of breast cancer patients results in a two- to sevenfold increased risk for development of endometrial cancer. Use of raloxifene, or the anti-estrogen ICI182780, does not result in such an increased risk. The objective of the current study was to generate and analyze gene expression profiles that reflect the transcriptional response of the human endometrium to estradiol, SERMs like tamoxifen and raloxifene, and anti-estrogens like ICI182780. METHODS: Transient transfections were performed to analyze the transcriptional response of ECC-1 cells to estradiol, tamoxifen, raloxifene, and ICI182780. Subsequently, to reveal the molecular mechanism of action, gene expression profiles were generated and some of the observed regulated genes were confirmed by Northern blotting. Biostatistical methods were employed to analyze the expression profile results further, and amphiregulin effects on ECC-1 cell signaling were investigated using Northern and Western blotting, and 3H-thymidine incorporation. RESULTS: Analysis of the profiles revealed that estradiol, tamoxifen, raloxifene, and ICI182780 influence the same biologic processes, but they do so via regulation of different sets of genes. Upon construction of a genetic network it was observed that the largest possible network centered on epidermal growth factor (EGF) receptor signaling. Furthermore, the EGF receptor ligand amphiregulin was differentially regulated by all four ligands. Next it was shown that amphiregulin indeed could stimulate EGF receptor signaling in ECC-1 cells. Based on these results, it was hypothesized that EGF receptor signaling could differentially be affected by estrogen, tamoxifen, raloxifene, and ICI182780 because these four compounds differentially regulate the EGF receptor ligand amphiregulin. CONCLUSIONS: Regulation of amphiregulin coincides with the described in vivo effect of the four ligands on the endometrium. Therefore, it is possible that modulation of EGF receptor signaling is a significant player in estrogen-agonistic growth of the endometrium and needs to be investigated further.

Amphiregulin↗
PubMed2003

[SERM and SARM].

There has been recent evidence about unfavorable effects of estrogen, while selective estrogen receptor modulators (SERM) with estrogen agonist and antagonist actions in a tissue selective manner have been developed. Among them, raloxifen inhibits the risk of vertebral fractures to a similar degree with bisphosphonates. From the same strategy, the study of selective androgen receptor modulators (SARM) has been in progress for the treatment of osteoporosis.

English Abstract↗
PubMed2004

Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer.

BACKGROUND: Antiestrogens of the selective estrogen receptor modulator (SERM) type, such as tamoxifen, have two major limitations: their mixed agonist and antagonist profile and the development of tumor resistance. We characterized two new pure antiestrogens-ZK-703 and ZK-253-that belong to the class of specific estrogen receptor destabilizers (SERDs), which includes fulvestrant, and compared their activity with that of fulvestrant and tamoxifen. METHODS: Effects of antiestrogens on the growth of estrogen-dependent breast tumors in vivo were determined using several mouse xenograft models (including the tamoxifen-sensitive tumors MCF7, T47D, and MV3366 and the tamoxifen-resistant tumors ZR75-1 and MCF7/TAM) and chemically induced (nitrosomethyl urea [NMU] and dimethylbenzanthracene [DMBA]) rat breast cancer models (groups of 10 animals). We determined the initial response and effects on hormone receptor levels and the time to relapse after treatment (i.e., time to reach a predetermined tumor size threshold). Estrogen receptor (ER) levels were determined by immunoassay. RESULTS: ZK-703 (administered subcutaneously) and ZK-253 (administered orally) were more effective than tamoxifen or fulvestrant at inhibiting the growth of ER-positive breast cancer in all xenograft models. For example, MCF7 tumors relapsed (i.e., reached the size threshold) in 10 weeks in mice treated with tamoxifen but in 30 weeks in mice treated with ZK-703. ZK-703 and ZK-253 also prevented further tumor progression in tamoxifen-resistant breast cancer models to a similar extent (more than 30 weeks in mice with ZR75-1 and MCF7/TAM tumors). In the chemically induced rat breast cancer models, orally administered ZK-703 and ZK-253 caused a nearly complete (>80%) inhibition of tumor growth. ER levels were dramatically reduced in MCF7 tumors after 5 weeks of ZK-703 treatment compared with ER levels in vehicle-treated tumors; by contrast, ER levels in tamoxifen-treated tumors were higher than those in control tumors. CONCLUSION: ZK-703 and ZK-253 are potent, long-term inhibitors of growth in both tamoxifen-sensitive and tamoxifen-resistant breast cancer models.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

[Study on the modulation of estrogen receptor isoforms alpha in endometrial carcinoma cells using antisense oligodeoxyribonucleotides].

OBJECTIVE: To verify the roles of estrogen receptor alpha in the tumogenesis of endometrial cancer in relationship with estrogen and tamoxifen, and to explore an efficient way to modulate the expression of estrogen receptor (ER) isoform alpha to built up a model of endometrial cancer cells expressing predominant one isoform of ERs for ultimately probing therapeutical and preventive antiestrogen for endometrial cancer. METHODS: A series of oligodeoxyribonucleotides against regions of the human ERalpha was synthesized and tested in human endometrial cancer cell line (HEC-1B cells) that expressed functional ERalpha. The expressions of ER isoforms were detected by Western blot using specific antibody. The change of HEC-1B cell proliferation in response to 17beta-estradiol(E2) and tamoxifen(TAM) under the impact of antisense oligodeoxyribonucleotides (AS-ODN) was studied. RESULTS: (1) Transfection with AS-ODN directed against the human ERalpha significantly inhibited ERalpha protein expression. (2) The proliferation of endometrial cancer cell line HEC-1B could be increased by both E(2) and TAM. The cells lost the ability to proliferate in response to E(2) after being transfected with ERalpha-AS-ODN at hours 24, 48 and 72. After being transfected with ERalpha-AS-ODN, HEC-1B cells lost the ability to proliferate in response to TAM at hour 48. CONCLUSION: (1) AS-ODNs directed against the human ERalpha can inhibit the expression of ER alpha effectively. The method can be used to built up a model of endometrial cancer cells expressing predominant one isoform of ERs. (2) ERalpha may be the primary receptor in the proliferation of HEC-1B cells in response to 17beta-estradiol and tamoxifen.

Cell Proliferation↗
PubMed2000

Symposium overview: estrogens and antiestrogens in managing the patient with breast cancer.

The prevalence of breast cancer (a hormonally driven neoplasm) in the United States, the potential health benefits of estrogen replacement therapy for postmenopausal women, and the burgeoning research focusing on selective estrogen receptor modulators (SERMs) have resulted in additional complexity in managing breast cancer. In an attempt to clarify existing data, the Society of Surgical Oncology sponsored a symposium entitled "Estrogens and Antiestrogens in Managing the Patient with Breast Cancer" at its 52nd Annual Cancer Symposium. This conference was held in March 1999 and was chaired by Dr. S. Eva Singletary, Professor of Surgery and Chief of the Surgical Breast Section at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. The following is a review of the material presented by the symposium participants.

Age Factors↗
PubMed2006

Prevention of breast cancer: current state of the science and future opportunities.

Despite significant progress in breast cancer treatment, mammary tumours still represent the second most frequent cause of cancer-related death in women in the US, with > 211,000 new cases in 2005; however, an expanding range of options for early diagnosis and more reliable risk assessment offers new alternatives for disease control by cancer prevention. Completed large studies with the classical selective estrogen receptor modulator (SERM) tamoxifen have demonstrated that preventing breast cancer pharmacologically is now possible. Novel SERMs, aromatase inhibitors and gonadotropin-releasing hormone agonists targeting hormonal pathways are being tested in clinical trials, revealing the potential for dramatic reductions in tumour incidence with minimal side effects; however, SERMs and aromatase inhibitors are effective only against estrogen receptor-positive tumours, thus chemopreventive drugs targeting other critical signalling pathways (such as retinoids, selective COX inhibitors and tyrosine kinase inhibitors) may provide a means to prevent estrogen receptor-negative breast cancer. In the future, hormonal and estrogen receptor-independent agents may be combined to prevent the development of all mammary tumours. This article reviews the current and novel strategies for breast cancer prevention.

Adenocarcinoma↗
PubMed2004

Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone.

UNLABELLED: Contradictory results whether the endocrine disrupters (ED) benzophenone-2 (BP2), bisphenol A (BPA) and dibutylphtalate (DBP) exert estrogenic effects have been published. Selective estrogen receptor modulators (SERMs) exert estrogenic effects in some but not in all organs and ED may be SERMs. Therefore, we studied their binding properties to recombinant ERalpha and ERbeta protein and their effects in the uterus, vagina and bone of ovariectomized rats. BP2 bound to both receptor subtypes, while BPA had a relatively high ERbeta selectivity. DBP did not bind to ERalpha but with a low affinity to ERbeta. In the uterus, only E2 and BP2 increased uterine weight and the complement C3 but decreased ERbeta gene expression. Discrete effects of BPA and DBP in the uterus were found upon histological examination. In the vagina, BP2 but not BPA and DBP had clear estrogenic effects. E2 and BP2 had antiosteoporotic effects in the metaphysis of the tibia. The serum surrogate parameters of bone metabolism, i.e. osteocalcin and the cross (rat) laps were significantly reduced by E2, an effect shared with BP2 but not by the two other EDs. THE CONCLUSION: BP2 acts as ERalpha and ERbeta agonist mimicking effects of E2, while the effects of BPA and DBP are not pure estrogenic.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor alpha expression is regulated by estrogen receptor alpha and modulates the response of MCF-7 cells to sodium butyrate.

Peroxisome proliferator-activated receptors are ligand-activated transcription factors with a potential role in cancer. We investigated peroxisome proliferator-activated receptor alpha expression in breast cancer cell lines and showed a relationship between mean peroxisome proliferator-activated receptor alpha and estrogen receptor alpha mRNA levels in estrogen receptor alpha positive breast cancer cells. Transfection of estrogen receptor alpha into the estrogen receptor alpha negative cell line, MDA-MB-231 decreased peroxisome proliferator-activated receptor alpha mRNA and conversely inhibition of estrogen receptor alpha by ICI-182 780 in estrogen receptor alpha positive, MCF-7 cells increased peroxisome proliferator-activated receptor alpha mRNA levels. Estrogen receptor alpha levels can be modulated by histone deacetylase inhibitors and such agents are in clinical trials for cancer treatment. We found the histone deacetylase inhibitor, sodium butyrate, increased peroxisome proliferator-activated receptor alpha mRNA levels within 4h of treatment. Peroxisome proliferator-activated receptor alpha modulation was independent of estrogen receptor alpha, as a similar increase was observed in the estrogen receptor alpha negative MDA-MB-231 cells. To further investigate the relationship between sodium butyrate and peroxisome proliferator-activated receptor alpha expression, we created an MCF-7 cell line that conditionally over-expresses human peroxisome proliferator-activated receptor alpha. Over-expression of the peroxisome proliferator-activated receptor protected MCF-7 cells from sodium butyrate-mediated inhibition of proliferation and attenuated sodium butyrate-mediated induction of histone deacetylase 3 mRNA, indicating that elevated levels of peroxisome proliferator-activated receptor alpha may reduce the sensitivity of cells to histone deacetylase inhibitors. The estrogen receptor alpha dependence of peroxisome proliferator-activated receptor alpha levels may be significant since estrogen receptor alpha negative breast cancer cells are associated with a more aggressive phenotype. Our studies also suggest that peroxisome proliferator-activated receptor alpha levels may be a marker of breast cancer cell sensitivity to histone deacetylase inhibitors.

Butyrates↗
PubMed2002

Tissue-specific estrogenic response and molecular mechanisms.

Estrogens exert profound effects on growth, differentiation, and function of many reproductive tissues. They also affect other tissues, including bone, liver, cardiovascular system, and brain. In the last few years it has been demonstrated that several synthetic estrogens can act in a tissue-specific manner. The first example of such a selective estrogen receptor modulator (SERM) was tamoxifen, for which an estrogen agonist-like activity in the endometrium and bone was seen to occur simultaneously with an estrogen antagonist activity in the breast. The mechanisms by which the same compound can exert tissue-specific agonist and antagonist actions are still being investigated. Important aspects include the interaction of the ligand with the two estrogen receptor subtypes and the interaction of these ligand-receptor complexes with effectors, which include different DNA response elements and important coregulator proteins. In addition to well-documented effects on gene transcription, there is evidence that estrogen receptors and other estrogen binding proteins are involved in some rapid, non-genomic effects of estrogens in target cells. For these reasons it is important to point out that a toxicological evaluation of endocrine modulators should include an analysis of potential SERM-like properties.

Animals↗
PubMed1986

Modulation of estrogen receptor by insulin and its biologic significance.

It has been proposed that a nonsteroidal hormone such as insulin may directly exert an influence through estrogen receptors and alter the biologic behavior of steroid hormone target tissue. The implication of such a proposal is that diabetes may alter the outcome of estrogen receptor-positive tumors such as breast or endometrial carcinomas. To evaluate the effect of insulin on a receptor-positive tumor, we examined the direct effect of insulin on an estrogen receptor and its subsequent biologic effect on a receptor-positive endometrial carcinoma model in vitro and in vivo. An in vitro experiment demonstrated that when the estrogen receptor-positive cell line was grown in serum-free media with low insulin, there was a loss of intracellular receptors for estrogen. This loss of estrogen receptors was also associated with increased growth rate as reflected by increased thymidine uptake. Similarly, in vivo experiments demonstrated that a diabetic host with a high blood glucose level and a low insulin level exhibited development of growth of a receptor-negative tumor with accelerated growth rate in contrast to growth of a receptor-positive tumor with slower growth rate in a normal host with normal serum insulin and blood glucose levels. Data suggest that insulin may modulate the growth of estrogen receptor-positive tumors through its direct effect on estrogen receptors.

Animals↗