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PubMed2000

Interaction of tetrahydrocrysene ketone with estrogen receptors alpha and beta indicates conformational differences in the receptor subtypes.

Estrogen receptors (ER) alpha and beta bind estradiol (E2) and other estrogenic ligands with different affinities. To measure the rate of E2 association with ERa and ERbeta, we employed tetrahydrocrysene ketone (THCK), a fluorescent ligand that is an agonist with ERalpha and an antagonist with ERbeta. We report that THCK binds E2-liganded and unliganded ERalpha and ERbeta, indicating a THCK binding site(s) other than the E2 binding pocket. THCK fluorescence was greater for ligand-occupied ERbeta than ERalpha, suggesting differences in the microenvironment of the THCK binding site(s). THCK fluorescence was also significantly greater for E2-, 4-hydroxytamoxifen-, and tamoxifen aziridine-liganded versus unliganded ER, allowing calculations of E2 association rate constants (ka) of 7.60 +/- 0.75 and 5.12 +/- 0.30 x 10(5) M(-1) s(-1) for E2-ERalpha and E2-ERbeta, respectively. THCK did not affect ERalpha binding to estrogen response element (ERE) DNA, but decreased ERbeta-ERE binding. We conclude that THCK binding site(s) on ERalpha versus ERbeta are different and important for ER function.

Animals↗
PubMed2003

Induction of p53 expression and function by estrogen in osteoblasts.

While estrogen's role in maintaining bone health relates to its action on osteoclasts, not much is presently known about the role of estrogen with respect to osteoblasts. Our laboratory is involved in studying the function of the p53 tumor suppressor gene in osteoblast differentiation. This study was therefore designed to understand the role of estrogen in osteoblast growth and differentiation and its effect on p53 function. ROS 17/2.8 cells, stably transfected with a construct containing multiple copies of a p53 response element fused to a chloramphenicol acetyl transferase (CAT) gene, were used to monitor wild-type p53 activity. Maximal p53 activity was observed when E2 was given at concentrations between 10(-12) and 10(-15) M. This increase in p53 activity was due to a change in transcription and peaked at about 16 hours after treatment. An increase in p53 activity was followed by an increase in expression of p53-regulated genes p21 and mdm2. This increase in p53 activity was partially inhibited by inclusion of estrogen antagonist ICI 182,780. Bone- specific markers osteocalcin and alkaline phophatase increased after treatment with E2, as did changes in estrogen receptors alpha and beta. Upregulation of osteocalcin was reduced when cycloheximide was added to E2, suggesting the presence of intermediates in the enhancement of osteocalcin gene transcription. These findings suggest that E2 can directly mediate an increase in p53 expression and function. The relevance of this to osteoblast differentiation is discussed.

Alkaline Phosphatase↗
PubMed2004

Antiestrogenic effects of motorcycle exhaust particulate in MCF-7 human breast cancer cells and immature female rats.

The emissions from 2- and 4-stroke motorcycles pollute the air of urban areas where motorcycle is a popular means of transportation. This study aimed to determine the endocrine-disrupting activity of motorcycle exhaust particulate (MEP) using MCF-7 human breast cancer cells and immature female Wistar rats treated with organic extracts of MEP. Treatments with 1, 10, and 50 microg/ml MEP extract for 2 and 4 days produced dose-dependent inhibition of thymidine incorporation and cell growth, respectively, in untreated and 1 nM 17beta-estradiol (E2)-treated cells. Treatments of MCF-7 cells with MEP extract replaced [3H]E2 from the estrogen receptor in a time- and concentration-dependent manner. These antiestrogenic and receptor binding properties of MEP extract were blocked by cotreatment of the cells with 2 microM alpha-naphthoflavone, a cytochrome P450 inhibitor and aryl hydrocarbon receptor antagonist. E2 metabolism and HPLC analysis showed that treatment of MCF-7 cells with 50 microg/ml MEP extract for 24 h increased E2 2- and 4-hydroxylation in microsomes. The MEP-mediated increase in E2 2-hydroxylation was inhibited by the addition of 1 microM alpha-naphthoflavone to MCF-7 microsomes. Cotreatment of immature female rats with 10 microg/kg E2 and 10 mg/kg MEP extract intraperitoneally for 3 days decreased the E2-induced uterine weights. MEP extract alone showed no effect on rat uterine weight. The endocrine-disrupting activity of MEP extract was further confirmed in parallel experiments using MCF-7 cells and immature female rats treated with benzo(a)pyrene, an MEP constituent compound. The present findings demonstrate that MEP extract is antiestrogenic in vitro and in vivo and cytochrome P450 induction is an underlying mechanism.

Air Pollutants↗
PubMed2004

Estimation of estrogenic and antiestrogenic activities of selected pesticides by MCF-7 cell proliferation assay.

Estrogenic activities of 20 selected pesticides-which are used for agricultural production as insecticides, fungicides and herbicides-were examined by estrogen receptor (ER)-dependent MCF-7 cell proliferation assay. Among them, chlordecone, dicofol, methoxychlor, gamma-HCH, fenarimol, EPN, triadimefon, and triadimenol had estrogenic activities, all of which were suppressed by the addition of pure antiestrogen ICI 182,780. The first 5 compounds exhibited binding capacities to ERalpha. The antiestrogenic activity of a compound was examined by estimating its suppressive effect on cell proliferation induced by 30 pM 17beta-estradiol. Strongly suspected antiestrogens were captan and myclobutanil, both of which were found to have the capacity to bind to ERalpha and which might exert their activities by competing at the level of ERalpha. Antiestrogenic activities of nitrofen, fenitrothion, fenarimol and triadimefon were also suggested. Affinities of the compounds for ERalpha and/or androgen receptor (AR) were lower than those of synthetic estrogen (diethylstilbestrol) and testosterone (mibolerone), respectively. Fenitrothion had the highest affinity to AR. Chlordecone, dicofol, methoxychlor, nitrofen, fenarimol, myclobutanil and pyridate had capacities to bind both ERalpha and AR. Chlordecone and pyridate were much more effective as competitors of estrogen binding to ERalpha than androgen binding to AR and, conversely, nitrofen was a more effective competitor of androgen binding to AR.

Binding, Competitive↗
PubMed2000

Radiolabeled estradiol derivatives to predict response to hormonal treatment in breast cancer: a review.

Several radiolabeled steroidal and nonsteroidal estradiol derivatives of which the tumoral uptake is believed to relate quantitatively to the content and binding characteristics of the alpha-estrogen receptor (alphaER) receptor in the target tissue have been synthesized and their imaging potential and clinical usefulness evaluated in vivo in humans. Due to the use of different methodologies and cut-off values for the measurement of alphaER positivity, the use of both quantitative positron emission tomography and semiquantitative single-photon emission tomography, and the difference in patient populations studied, direct comparison of these data is not possible. Individual data, however, fail to substantiate a direct relationship between these radiolabeled estradiol derivatives and alphaER status, in keeping with recent pathophysiological findings demonstrating (1) estradiol sequestration and retention through other than alphaER-mediated, either membrane- or non-membrane-related, mechanisms and (2) an inverse relationship between estradiol uptake and local biosynthesis through aromatization and interconversion in alphaER-positive tumors. Additionally, given the discovery of very high affinity alphaER-like binding sites (Kd, dissociation constant, <0.1 nM), and the potential for underestimation of aER Kd when using ligand binding assays, at least part of the radiolabeled estradiol derivative uptake reflects tumoral perfusion rather than the ligand-receptor binding process. However, the reduction in cellular uptake, membrane sequestration and local biosynthesis of estradiol following tamoxifen treatment in alphaER-responsive tumors should allow early prediction of response to therapy through rapid sequential radiolabeled estradiol scintigraphy with higher accuracy than conventional alphaER estimations, as supported by recent data.

Binding Sites↗
PubMed2004

Expression of estrogen receptors-alpha and -beta in primary breast neoplasms and tumors exposed to neoadjuvant hormonal therapy.

We studied the content and expression of mRNA for estrogen receptors-alpha and -beta in breast tumors before and after 3-month neoadjuvant hormone therapy with antiestrogen tamoxifen and/or aromatase inhibitors. Expression of estrogen receptors-alpha and -beta was most often detected in ER+PR+ tumors and most significantly decreased in these neoplasms after exemestane therapy. Immunocytochemical and radioligand assays showed that tamoxifen and anastrozole have little effect on the number of estrogen receptors-alpha. The number of progesterone receptors in tumors decreased by the end of anastrozole therapy. Estrogen receptors-beta were immunocytochemically revealed in 50% primary breast tumors. Anastrozole slightly decreased, while tamoxifen increased the incidence of these receptors. Interruption of signaling through estrogen receptors and suppression of estrogen biosynthesis had different effects on the receptor status of neoplasms and distribution of estrogen receptors-alpha and -beta.

Anastrozole↗
PubMed2006

Multiple hormonal activities of UV filters and comparison of in vivo and in vitro estrogenic activity of ethyl-4-aminobenzoate in fish.

UV filters have been detected in surface water, wastewater and fish, and some of them are estrogenic in fish. At present, little is known about their additional hormonal activities in different hormonal receptor systems despite their increasing use and environmental persistence. Besides estrogenic activity, UV filters may have additional activities, both agonistic and antagonistic in aquatic organisms. In our study, we investigate a series of UV filters for multiple hormonal activities in vitro in human receptor systems and evaluate the predictive value of these findings for the activity in fish in vitro and in vivo. First we systematically analysed the estrogenic, antiestrogenic, androgenic, and antiandrogenic activity of 18 UV filters and one metabolite in vitro at non-cytotoxic concentrations with recombinant yeast systems carrying either a human estrogen (hERalpha) or androgen receptor (hAR). All 19 compounds elicited hormonal activities, surprisingly most of them multiple activities. We found 10 UV-filters having agonistic effects towards the hERalpha. Surprisingly, we identified for the first time six UV filters with androgenic activities and many of them having pronounced antiestrogenic and antiandrogenic activities. As much as 17 compounds inhibited 4,5-dihydrotestosterone activity in the hAR assay, while 14 compounds inhibited estradiol activity in the hERalpha assay, indicating antiandrogenic and antiestrogenic activity, respectively. In particular, the antiandrogenic activities of phenyl- and benzyl salicylate, benzophenone-1 and -2, and of 4-hydroxybenzophenone were higher than that of flutamide, a known hAR antagonist. In a second series of experiments, we investigated the predictive power of the hERalpha assay for aquatic organisms by further investigating the estrogenic UV filter ethyl 4-aminobenzoate (Et-PABA) in vitro and in vivo in fish. Et-PABA showed estrogenic activity in a recombinant yeast system carrying the rainbow trout estrogen receptor (rtERalpha) with higher activity than in the hERalpha assay. In addition, Et-PABA induced vitellogenin after 14 days of exposure in juvenile fathead minnows at 4394mug/L. Our study shows estrogenic activity of this UV filter in fish both in vitro and in vivo. In conjunction with in vitro human receptor-based systems our results give a more detailed picture about distinct hormonal activities of UV filters occurring in aquatic systems. We conclude that receptor-based assays are important for in vitro assessment of UV-filters prior to or concurrently with in vivo assays, which ultimately provide data for the environmental risk assessment of these important personal care products.

Androgen Antagonists↗
PubMed2004

Electrochemical detection of xenoestrogenic and antiestrogenic compounds using a yeast two-hybrid-17-beta-estradiol system.

The goal of this study was to determine the effects of various compounds on the 17-beta-estradiol-induced dimerization of the human estrogen receptor alpha (hERalpha), a nuclear transcription factor. For this purpose, we used a modified yeast two-hybrid (YTH) bioassay designed to study protein-protein interactions, based on the electrochemical monitoring of hERalpha dimerization and detected as beta-D-galactosidase reporter gene activity in a synthetic substrate p-aminophenyl-beta-D-galactopyranoside (pAPG). Compared with 17-beta-estradiol activity, genistein, bisphenol-A (BPA), and naringenin induced dimerization to a lower extent by four, five and six magnitudes of orders of magnitude, respectively. In the presence of physiological concentrations of 17-beta-estradiol, both tamoxifen and the analgesic drug acetaminophen inhibited hER dimerization in an antiestrogenic manner.

Acetaminophen↗
PubMed2004

Insulin-like growth factor-I receptor and estrogen receptor crosstalk mediates hormone-induced neurite outgrowth in PC12 cells.

Estradiol (E(2)) and insulin-like growth factor-I (IGF-I) can act independently or in concert to promote neurite outgrowth in vivo and in cultured neurons. This study examined the role of crosstalk between estrogen receptor (ER)alpha and the IGF-I receptor as a critical mediator of hormone- and growth factor-dependent neurite outgrowth in a homogenous cell system. We used control PC12 cells and PC12 cells stably transfected with ER alpha, both of which express IGF-I receptor. Cells were treated for 1 week with vehicle, 1 nM E(2) or 100 ng/ml IGF-I alone or with E(2) or IGF-I in the presence of either the IGF-I receptor antagonist JB1 or the ER antagonist ICI 182,780. IGF-I significantly increased neurite outgrowth, as measured by the percentage of process-bearing cells, and absolute neurite length per cell in both control and ER alpha-transfected PC12 cells. In contrast, E(2) increased process formation and extension only in PC12 cells that were stably transfected with ER alpha. ICI 182,780 and JB1 blocked the IGF-I-induced increases in neurite length in both cell types. The efficacy of ICI 182,780 in control PC12 cells may have been due to the upregulation of ER alpha in these cells by the 7-day treatment with IGF-I. The ER and IGF-I receptor antagonists similarly blocked the E(2)-induced increase in neurite lengths in ER alpha-transfected cells. Immunofluorescent analysis of the cellular distribution of an axonal marker, phospho-neurofilament, verified that the processes extended by PC12 cells were neurites. These data suggest that receptor crosstalk between IGF-I receptors and ER alpha has an important role in neurite formation and extension even in a single-cell system.

Animals↗
PubMed2004

Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer.

Using a novel approach that detects changes in the conformation of ERalpha, we studied the efficacy of anti-estrogens to inactivate ERalpha under different experimental conditions. We show that phosphorylation of serine-305 in the hinge region of ERalpha by protein kinase A (PKA) induced resistance to tamoxifen. Tamoxifen bound but then failed to induce the inactive conformation, invoking ERalpha-dependent transactivation instead. PKA activity thus induces a switch from antagonistic to agonistic effects of tamoxifen on ERalpha. In clinical samples, we found that downregulation of a negative regulator of PKA, PKA-RIalpha, was associated with tamoxifen resistance prior to treatment. Activation of PKA by downregulation of PKA-RIalpha converts tamoxifen from an ERalpha inhibitor into a growth stimulator, without any effect on ICI 182780 (Fulvestrant).

Antineoplastic Agents, Hormonal↗
PubMed2003

Mechanisms governing the accumulation of estrogen receptor alpha in MCF-7 breast cancer cells treated with hydroxytamoxifen and related antiestrogens.

This study aimed at a better understanding of estrogen receptor alpha (ER) up regulation induced by partial estrogen antagonists. Effect of treatment with hydroxytamoxifen (OH-Tam) on ER level in MCF-7 cells was investigated by an approach combining ER measurement (enzyme immunoassay) and morphological demonstration (immunofluorescence). Furthermore, the influence of drug exposure on the rates of ER synthesis and degradation was assessed by determining [35S]methionine incorporated into the receptor in different experimental conditions (measurement of synthesis or pulse-chase experiments). ER up regulation was already induced by a 1-h pulse treatment with OH-Tam, thus a continuous exposure was not required. This process appeared reversible (i.e. ER accumulation due to OH-Tam rapidly vanished upon subsequent exposure to 17beta-estradiol (E2) or the pure antiestrogen RU 58668). While OH-Tam did not affect the rate of [35S]methionine incorporation into ER, it clearly caused an impairment of ER degradation (pulse-chase experiments) indicating that up regulation results from a stabilization of the receptor associated with the maintenance of its synthesis. Various tamoxifen derivatives, as well as a few related partial antiestrogens, were compared on the basis of binding ability and propensity to induce ER up regulation. A close relationship was found between both properties. Structure-activity analysis revealed that the capacity of these compounds to induce ER up regulation is associated with characteristics of their aminoalkyle side-chain, similar to those required for antiestrogenicity.

Breast Neoplasms↗
PubMed2005

2,5-Diphenylfuran-based pure antiestrogens with selectivity for the estrogen receptor alpha.

The estrogen receptor alpha (ERalpha) is understood to play an important role in the progression of breast cancer. Therefore, pure antiestrogens with a preference for this receptor form are of interest as new agents for the treatment of this malignancy. Several chemical structures with selective binding affinity for ERalpha have been identified and might be useful for the synthesis of ERalpha-selective pure antiestrogens. In this study we applied the 2,5-diphenylfuran system which is closely related to the triphenylfurans described by others. Various side chains with amino and/or sulfur functions were linked to C3 to convert the furans to estrogen antagonists without residual estrogenic activity. The degree of alpha-selectivity which ranges from 2.5- to 236-fold is strongly influenced by the alkyl group at C4. Antiestrogenic potency was determined in MCF-7/2a breast cancer cells stably transfected with a luciferase gene under the control of an ERE. The 2,5-bis(4-hydroxyphenyl)furan with an ethyl substituent and a 6-[N-methyl-N-(3-pentylthiopropyl)amino]hexyl side chain exerted the strongest antiestrogenic effect in this series with an IC(50) value of 50 nM in cells stimulated with 1 nM estradiol. The RBA values of this derivative were 18% (ERalpha) and 3.4% (ERbeta) of estradiol, respectively. It inhibited the growth of wild-type MCF-7 cells with an IC(50) value of 22 nM. The data show that the 2,5-diphenylfuran system is appropriate for the development of pure antiestrogens with preference for ERalpha.

Animals↗
PubMed2006

Decreased responsiveness of naturally occurring mutants of human estrogen receptor alpha to estrogens and antiestrogens.

Estrogen receptor alpha (ERalpha) is a ligand-inducible transcription factor that mediates the biological effects of estrogens and antiestrogens. Many point mutations in the human ERalpha gene have been reported to be associated with breast cancer, endometrial cancer, and psychiatric diseases. However, functional analyses for most mutants with amino acid changes are still lacking. In the present study, to investigate the effects of point mutations on the function, gel-shift assays and luciferase assays were performed for eight kinds of mutated ERalpha proteins, including a single nucleotide change of C207G (N69K), G478T (G160C), T887C (L296P), A908G (K303R), C926T (S309F), A1058T (E353V), A1186G (M396V), and G1231deletion (411fsX7). The mutated ERalpha expression plasmids were constructed by site-directed mutagenesis. With gel-shift assays using in vitro translated ERalpha proteins, binding to the consensus estrogen response element (ERE) was observed for the mutated ERalpha proteins except ERalpha (G160C) and ERalpha (411fsX7), the binding of which was comparable with that of the wild type. Western blot analyses showed that ERalpha (G160C) could not be efficiently translated with the in vitro transcription/translation system and that ERalpha (411fsX7) produced a truncated protein. To investigate the transactivation potency, wild-type or mutated ERalpha expression plasmids were co-transfected with pGL3-3EREc38 reporter plasmid into human breast adenocarcinoma MDA-MB-435 cells. The concentration-response curves (10pM-100nM E2) of the mutant ERalpha proteins except ERalpha (E353V) and ERalpha (411fsX7) were similar to that of wild-type ERalpha. However, at a low level of E2 (100pM), the mutants ERalpha (N69K), ERalpha (L296P), ERalpha (S309F), and ERalpha (M396V) showed a significant decrease of transactivation compared with that of the wild-type ERalpha. The mutants ERalpha (E353V) and ERalpha (411fsX7) did not show responsiveness to E2 and antiestrogens, 4-hydroxytamoxifen (4OHT) and ICI 182,780. The mutant ERalpha (S309F) showed decreased responsiveness for the antiestrogenicity of 4OHT. In conclusion, we found that some of the naturally occurring human ERalpha mutants with amino acid changes may have an altered responsiveness to estrogen and antiestrogens.

Amino Acid Substitution↗
PubMed2005

Gene expression changes in rat prostate after activation or blocking of the androgen and estrogen receptor.

Several endpoints of different molecular complexity were studied in the Hershberger assay in order to evaluate the specificity and suitability of this test as a broad screening model. Androgen and estrogen receptors were activated or blocked, and expression of typical estrogen- or androgen responsive genes (complement C3, ERalpha, ERbeta, AR, TRPM-2, PBP C3, ODC, and IGF-1 mRNA) was analyzed in rat ventral prostate by real time RT-PCR. Administration of estradiol benzoate (EB) to castrated testosterone-treated rats had no effect on reproductive organ weights or gene expression levels and the anti-estrogen, ICI 182780, only affected ODC expression. Therefore, estrogenic or anti-estrogenic compounds would not be expected to seriously affect the outcome of a Hershberger test. However, EB given alone to castrated rats resulted in various effects. EB increased seminal vesicle weight, an effect reversed by ICI 182780, and affected TRPM-2, PBP C3, ODC, IGF-1, AR, and ERalpha mRNA levels. AR expression in the prostate seemed to be under regulation of both estrogens and androgens, as ICI 182780 inhibited the testosterone-induced AR expression, and flutamide inhibited the EB-induced AR expression. These data indicate that estrogens have various effects in castrated male rats and that expression of several genes is under multi-hormonal control in the ventral prostate. However, interactions between estrogens and androgens do not play a major role in the Hershberger assay, as simultaneous TP administration abolished the effects of EB. First choice of gene expression profiles in the Hershberger assay to study androgenic or anti-androgenic effects would be the traditional, TRPM-2 and PBP C3, supplemented with the new complement C3.

Androgen Receptor Antagonists↗
PubMed2004

The neuroprotective effects of estrogen in SK-N-SH neuroblastoma cell cultures.

Estrogen has been considered to be a neuroprotectant and a neuromodulator in many neuronal cell lines and tissue preparations. The protective effects of estrogen may be mediated through classical estrogen receptors (ERs), or may be due to its anti-oxidant properties which are independent of receptors. The current studies show that 17beta-estradiol (E2) is neuroprotective against beta-amyloid protein 25-35 (Abeta)-, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-, high density culture condition-, and serum deprivation-induced neuronal death in SK-N-SH human neuroblastoma cells. SK-N-SH cells express ERbeta, but not ERalpha, as detected by Western blot analysis. Among all the insults, MPTP, high density culture and serum deprivation induce apoptotic cell death in this cell system as detected by ELISA determination of mono/oligonucleosomes and DNA laddering, while Abeta induces necrotic cell death. The protective effects of E2 are abolished by the addition of tamoxifen and ICI 182,780 in the MPTP treated cells, but not in the other models, suggesting that the effect of E2 in the MPTP model is probably associated with activation of ERbeta. The addition of ICI 182,780 shows a mitogenic effect in SK-N-SH cells in the presence of E2 in control culture or in the Abeta treated groups. Also, ICI 182,780 induced expression of ERalpha. Collectively, the current studies suggest that E2 is neuroprotective in apoptotic and necrotic death induced by multiple insults in SK-N-SH human neuroblastoma cells. Involvement of ER is insult type dependent. ICI 182,780 is able to influence the expression of ERs, probably through upregulation of ERalpha when ERbeta is totally antagonized.

Cell Line, Tumor↗
PubMed2005

Effects of selective estrogen receptor agonists on food intake and body weight gain in rats.

Ovariectomized (OVX) rats eat more and gain weight more rapidly than sham-operated (SO) rats and estradiol (E(2)) treatment attenuates food intake and body weight gain in OVX rats. Studies were designed to test the hypothesis that the alpha subtype of the estrogen receptor (ERalpha) mediates the attenuating effects of E(2) on food intake and body weight gain while the beta subtype (ERbeta) mediates opposing actions that lead to increased food intake and body weight gain. Female rats were SO or OVX and treated daily with vehicle (dimethylsulfoxide, DMSO) or E(2) (10 microg/day), or the ERalpha-selective agonist, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 0.5 mg/day), or the ERbeta-selective agonist, 2,3-bis(4-hyroxyphenyl)-propionitrile (DPN, 0.5 mg/day) for 14 days. Total food intake was significantly reduced by E(2) and PPT, but not DPN. Total body weight gain was significantly increased in OVX rats compared to SO rats and treatment with E(2) or PPT, but not DPN, significantly decreased total body weight gain to levels that were not significantly different from SO rats. A dose-response study of PPT indicated that at 0.25 mg/day, PPT significantly reduced total 21-day food intake and body weight gain and, at 0.13 and 0.06 mg/day, PPT significantly reduced total body weight gain compared to OVX rats without significantly reducing total food intake. A dose-response study of DPN indicated that none of the three doses of DPN significantly altered total 21-day food intake or total body weight gain. These results suggest ERalpha mediates the attenuating effects of estrogens on food intake and body weight gain while ERbeta has no effect on these variables.

Animals↗
PubMed2000

Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that activates the aryl hydrocarbon receptor (AhR) and disrupts multiple endocrine signaling pathways. T47D human breast cancer cells express a functional estrogen receptor alpha (ERalpha) and AhR, and treatment of these cells with 17beta-estradiol (E2) or TCDD resulted in a rapid proteasome-dependent decrease in immunoreactive ERalpha and AhR proteins (>60-80%), respectively. E2 did not affect the AhR, whereas TCDD induced proteasome-dependent degradation of both the AhR and ERalpha in T47D and MCF-7 human breast cancer cells, and these responses were specifically blocked by proteasome inhibitors. Thus, TCDD-induced degradation of ERalpha may contribute to the antiestrogenic activity of AhR agonists and this pathway may be involved in AhR-mediated disruption of other endocrine responses.

Breast Neoplasms↗
PubMed2003

Receptor profiling and endocrine interactions of tibolone.

The receptor profiles and in vivo activity of tibolone, and its primary metabolites, Delta(4)-isomer, and 3alpha- and 3beta-hydroxytibolone, were studied and compared to those of structurally related compounds. The Delta(4)-isomer was the strongest binder and activator of the progesterone receptor (PR); tibolone was 10 times weaker in binding and half as potent in transactivation of PR; 3alpha- and 3beta-hydroxytibolone did not bind or activate PR. In rabbits oral tibolone produced a minor progestagenic effect in the endometrium, whereas co-administration of tibolone and the anti-estrogen ICI 164,384 unmasked tibolone's progestagenic effect. 3-Hydroxytibolones were the strongest binders and activators of the estrogen receptors (ERs), with greater affinity for ERalpha than for ERbeta. Tibolone showed weaker binding and activation of both ERs and the Delta(4)-isomer has a binding and activation activity of less than 0.1% of E2 for ERalpha or ERbeta. Tamoxifen and 4-hydroxytamoxifen showed partial ERalpha agonistic effects with a maximal response of 12% and raloxifene of 3-5%. Oral administration of 1mg tibolone to ovariectomized rats induced an estrogenic effect on vaginal epithelium. The Delta(4)-isomer was a stronger binder and activator of the androgen receptor (AR) than tibolone; both 3-hydroxytibolones did not bind or activate AR. Introducing a 7alpha-methyl group decreased progestagenic and increased androgenic activity. We conclude that the progestagenic and androgenic activities of tibolone are mediated by the Delta(4)-isomer, and the estrogenic activity, by the 3-hydroxytibolones. The estrogenic activity of the 3-hydroxytibolones masked the progestagenic activity of tibolone in rabbit endometrium. Full estrogenic response was observed in rat vaginal tissue after oral administration of tibolone.

Animals↗