Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of 17 beta-estradiol, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and their combination on the metabolism of [1-13C] glucose were determined in cell suspensions of wild-type MCF-7 human breast cancer cells, by 13C NMR spectroscopy. Preliminary studies showed that, during the 7-hr duration of the NMR experiment, the cells maintained their viability and their aryl hydrocarbon responsiveness. Lactate was the major glucose metabolite detected in these studies, and the rate of lactate formation in the untreated (control) and 17 beta-estradiol (10(-9) M)-treated cells was 60 and 86 fmol/cell/hr, respectively; this represented a 40% increase in lactate formation in the cells treated with 17 beta-estradiol; comparable results were observed for the percentage of glucose converted into lactate. In contrast, TCDD (10(-9) M) did not significantly alter the rate of glucose metabolism or lactate formation. Co-treatment of the cells with 17 beta-estradiol (10(-9) M) plus TCDD (10(-8) to 10(-10) M) showed that TCDD completely inhibited the 17 beta-estradiol-induced metabolism of [13C] glucose to lactate in MCF-7 cells. In contrast, 2,8-dichlorodibenzo-p-dioxin (10(-8) M), a weak aryl hydrocarbon receptor agonist, did not inhibit estrogen-induced glucose-to-lactate metabolism in MCF-7 cells. In addition, it was shown that TCDD caused a significant decrease in 17 beta-estradiol-induced lactate formation within 1 hr after treatment, whereas the induction of monooxygenase activity was not observed until 3 hr after exposure of the cells to TCDD. These data indicate that TCDD-induced 17 beta-estradiol metabolism is not related to the decrease in the rate of conversion of glucose to lactate. These results further define the antiestrogenic responses elicited by TCDD and show that 13C NMR spectroscopy provides a unique method for measuring, in real time, the effects of TCDD on specific metabolic pathways.
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PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17 beta-estradiol-induced glucose metabolism in MCF-7 human breast cancer cells: 13C nuclear magnetic resonance spectroscopy studies. 175 38

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Environmental and dietary estrogens and human health: is there a problem? 749 80

Human breast cancer cell lines are widely used to study the antiestrogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vitro. Like other groups we found that 10 nM TCDD inhibits cell growth and induces cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) activity in MCF-7 cells expressing the estradiol receptor (ER). Neither cell growth nor EROD activity was affected in ER-negative MDA-MB 231 cells. Results of reverse transcription-polymerase chain reaction (RT-PCR) revealed a strong induction of CYP1A1 mRNA in MCF-7 but only a weak increase in MDA-MB 231 cells treated with 1, 10, or 100 nM TCDD. Transcripts of CYP1B1 were detected in both cell lines and mRNA content was enhanced 8- and 30-fold in MCF-7 and MDA-MB 231 cells treated with 1 nM TCDD, respectively. In gel mobility shift assay a stronger signal of DNA-binding aryl hydrocarbon receptor (AhR) was observed in MDA-MB 231 than in MCF-7 cells treated with 10 nM TCDD. These results were confirmed by RT-PCR analyses which showed an approximately 40-fold higher AhR mRNA content in untreated MDA-MB 231 than in MCF-7 cells. In contrast the mRNA of the AhR nuclear translocator was expressed in a similar range of magnitude. Treatment of the cells with TCDD did not change mRNA expression of both genes. Analysis of NADPH:quinone oxidoreductase (NMO-1) and plasminogen activator inhibitor-2 (PAI-2) mRNA expression revealed a dose-dependent induction of both genes in MDA-MB 231 cells after TCDD-treatment. From the results it was concluded that AhR-mediated transactivation is not impaired in ER-negative MDA-MB 231 cells. In addition, the results confirm reported data that expression of ER seems to be important for regulation of CYP1A1 induction after TCDD in human breast cancer cell lines but the present data show that ER does not appear to have a function in TCDD-induced mRNA expression of CYP1B1, NMO-1, and PAI-2 in MDA-MB 231 cells.
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PMID:Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. 764 66

Both retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicit a number of common biochemical and toxic responses including teratogenic effects in mice and inhibition of cell proliferation of numerous cell lines. In mice, RA plus TCDD interact synergistically as teratogens, suggesting a link between the RA and aryl hydrocarbon receptor signal transduction pathways. In this study, it was shown that both RA and TCDD elicit a number of common responses in MCF-7 human breast cancer cells, including inhibition of estrogen-induced cell proliferation and [3H]thymidine uptake, inhibition of nuclear estrogen receptor (ER) ligand binding, and interactions with a consensus [32]estrogen-responsive element in a gel mobility shift assay. RA and TCDD also decrease steady-state ER mRNA levels in a time-dependent manner. Moreover, interactive studies in which cells were treated with both RA plus TCDD also resulted in decreased responses.
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PMID:Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid in MCF-7 human breast cancer cells. 804 42

Treatment of MCF-7 human breast cancer cells with 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) did not decrease prolactin receptor (PRLR) binding. In contrast, PRLR mRNA levels were significantly decreased within 12 h after treatment with TCDD and persisted for up to 48 h. The effects of TCDD on PRLR mRNA levels were inhibited by the aryl hydrocarbon (Ah) receptor antagonist alpha-naphthoflavone and were not observed in Ah nonresponsive benzo[alpha]pyrene-resistant MCF-7 cells. These results suggest that the effects of TCDD were mediated through the Ah receptor. After treatment of MCF-7 cells with 10 nM 17 beta-estradiol (E2), there was a 2.3-fold increase in PRLR mRNA levels, and in cells cotreated with E2 plus TCDD, there was a 72% decrease in E2-induced PRLR mRNA levels. Previous studies have showed that TCDD also effects estrogen receptor (ER) binding and mRNA levels through the aryl hydrocarbon receptor pathway; however, the effects of TCDD on PRLR levels and binding in MCF-7 cells were different from those previously observed for ER.
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PMID:Inhibition of prolactin receptor gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 human breast cancer cells. 880 6

Polychlorinated biphenyls (PCBs) are one of the most widespread, persistent man-made products in the ecosystem giving rise to serious environmental contamination and potential hazard to health. The PCBs, in common with other compounds such as the dioxins, have been shown to exert some biological actions mediated through the aryl hydrocarbon receptor. Evidence for interaction of PCBs with other nuclear receptors has been sparse. Here we present evidence that 3,4,3',4'-tetrachlorobiphenyl (TCB) (PCB77), a PCB with high toxicity and significant bioaccumulation, can act as an estrogen with actions mediated through the estrogen receptor. Evidence is presented from multiple assay systems including 1) ligand binding to estrogen receptor in a competitive binding assay, 2) ligand ability to induce estrogen receptor binding to DNA, 3) ligand regulation of gene expression from a transfected exogenous (ERE-tk-CAT) or an endogenous (pS2) estrogen-regulated gene, 4) ligand regulation of cell growth in estrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1, and 5) ligand activity in the immature mouse uterine weight bioassay in vivo. These results demonstrate that TCB (PCB77) can be included in the increasing list of environmental pollutants that possess the ability to mimic estrogen action and be termed an environmental estrogen. Since the concentrations of TCB used here (10(-9) M; 292 ng/liter) are not incompatible with levels of PCB/TCB found in human tissues, these results may have physiological relevance. Use of multiple approaches to study estrogenic action demonstrates that one congener can act as both an agonist and antagonist of estrogen action and that the magnitude of these effects can alter according to the molecular environment.
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PMID:3,4,3',4'-Tetrachlorobiphenyl acts as an estrogen in vitro and in vivo. 884 9

The estrogen receptor and aryl hydrocarbon receptor (AhR) are coexpressed in several Ah and estrogen-responsive human breast cancer cell lines. However, a recent study reported that 17beta-estradiol (E2) inhibited Ah responsiveness in mouse Hepa 1c1c7 hepatoma cells (Kharat, I., and Saatcioglu, F. (1996) J. Biol. Chem. 271, 10533-10537), and therefore, estrogen receptor-AhR cross-talk was reinvestigated in MCF-7 and mouse Hepa 1c1c7 cells. Treatment of MCF-7 or Hepa 1c1c7 cells with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in induction of CYP1A1-dependent activity and mRNA levels. Treatment of both cell lines with E2 had no effect on basal or TCDD-inducible CYP1A1-dependent activity or mRNA levels. In MCF-7 and Hepa 1c1c7 cells transiently transfected with an Ah-responsive plasmid containing the 5'-regulatory region of the human CYP1A1 gene fused to the chloramphenicol acetyltransferase reporter gene 10 nM TCDD significantly induced chloramphenicol acetyltransferase activity; in cells cotreated with TCDD plus E2 the induced response was not affected by the hormone. Nuclear extracts from cells treated with dimethyl sulfoxide, E2, TCDD, and TCDD plus E2 were incubated with the [32P]dioxin-responsive element and analyzed by gel electrophoretic mobility shift assays. A retarded band associated with formation of a [32P]dioxin-responsive element-AhR complex was observed in nuclear extracts from cells treated with TCDD or TCDD plus E2 (cotreated). Collectively these studies suggest that E2 does not modulate AhR-mediated CYP1A1 gene expression in MCF-7 or Hepa 1c1c7 cells.
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PMID:Estrogen does not inhibit 2,3,7, 8-tetrachlorodibenzo-p-dioxin-mediated effects in MCF-7 and Hepa 1c1c7 cells. 937 12

17beta-Estradiol (E2) induces cathepsin D gene expression in MCF-7 human breast cancer cells and previous analyses of the proximal promoter region of this gene identified two functional enhancer sequences; namely an Sp1(N)23estrogen-responsive element (ERE) half-site (-199 to -165) and an imperfect palindromic ERE (-119 to -107). A third region of the cathepsin D gene promoter (CD/L, -145 to -119) was also E2 responsive in transient transfection assays. A GC-rich sequence which contains two overlapping Sp1 binding sites (-145 to -135) was responsible for ER-mediated transactivation and required formation of an ER/Sp1 complex in which only the Sp1 protein bound DNA. E2 responsiveness of the CD/L sequence was also dependent on an adjacent overlapping GCGTG motif corresponding to the dioxin-responsive element (DRE) core binding sequence, which is the cognate response element for the heterodimeric aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) transcription factor complex. The results show that ER-mediated transactivation of CD/L was associated with the Sp1(N)2-4DRE (core) motif and involved formation of a multiprotein ER/Sp1-AhR/ARNT complex. These results illustrate a unique example of an endogenous role for AhR/ARNT in the absence of added AhR agonist and indicate that the cathepsin D gene proximal promoter region contains at least three different functional motifs associated with ER-mediated transactivation.
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PMID:Functional and physical interactions between the estrogen receptor Sp1 and nuclear aryl hydrocarbon receptor complexes. 961 Dec 53

Phytochemicals such as indole-3-carbinol (I3C) and sulforaphane are components of cruciferous vegetables which exhibit antitumorigenic activity associated with altered carcinogen metabolism and detoxification. Diindolylmethane (DIM) is a major acid-catalyzed metabolite of I3C formed in the gut that binds to the aryl hydrocarbon receptor (AhR) and treatment of MCF-7 human breast cancer cells with 10-50 microM DIM resulted in rapid formation of the nuclear AhR complex and induction of CYP1A1 gene expression was observed at concentrations >50 microM. Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AhR ligand, inhibits 17beta-estradiol (E2)-induced responses in MCF-7 cells and growth of E2-dependent 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Results of this study show that like TCDD, DIM inhibits E2-induced proliferation of MCF-7 cells, reporter gene activity in cells transiently transfected with an E2-responsive plasmid (containing a frog vitellogenin A2 gene promoter insert) and down-regulates the nuclear estrogen receptor. Moreover, DIM (5 mg/kg every other day) also inhibits DMBA-induced mammary tumor growth in Sprague-Dawley rats and this was not accompanied by induction of hepatic CYP1A1-dependent activity. Thus, DIM represents a new class of relatively non-toxic AhR-based antiestrogens that inhibit E2-dependent tumor growth in rodents and current studies are focused on development of analogs for clinical treatment of breast cancer.
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PMID:Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. 977 35

The ability of a methylene chloride extract of diesel exhaust particle (EDEP) to activate the aryl hydrocarbon receptor (AhR), bind to and activate the estrogen receptor (ER), and induce gene expression mediated via these nuclear receptors was examined in Hepa1c1c7 mouse hepatoma and MCF-7 human breast cancer cells. EDEP was able to induce a protein-DNA complex by gel retardation assays using a [gamma-32P]dATP-labeled dioxin response element (DRE). This complex could be effectively competed by a 150-fold excess of unlabeled DRE but not by a 150-fold excess of unlabeled mutated DRE. In Hepa1c1c7 cells that were transiently transfected with a DRE-regulated luciferase reporter gene, 4.6 ng/microliter EDEP treatment for 24 h resulted in a 22-fold induction of luciferase activity. In the same cell line, ethoxyresorufin-O-deethylase activity was significantly induced 20-fold following 24 h treatment with 4.6 ng/microliter EDEP. Using a competitive ligand binding assay, EDEP displaced bound tritiated E2 from the rat uterine ER in a dose-dependent manner with an IC50 of approximately 100 ng/microliter compared to the IC50 of E2, which was approximately 4.4x10(-4) ng/microliter (1.6 nM). In MCF-7 human breast cancer cells transiently transfected with a Gal4-regulated luciferase reporter gene (17m5-G-Luc) and a chimeric ER (Gal4-HEG0), treatment with 4.6 ng/microliter EDEP for 24 h resulted in a three-fold increase in luciferase activity (P<0.01) compared with the seven-fold increase observed with E2. This study demonstrates that EDEP is able to activate the AhR and ER and induce transcription of reporter genes regulated by these receptors' DNA response elements. Further study is required to identify the individual compound(s) responsible for the observed activity.
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PMID:Ah receptor and estrogen receptor-dependent modulation of gene expression by extracts of diesel exhaust particles. 984 10


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