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)

Transcriptional activation of the human CYP1A1 gene (coding for cytochrome P450 1A1) is mediated by the aryl hydrocarbon receptor (AhR). In the present study we have examined the effect of the common dietary polyphenolic compounds quercetin and kaempferol on the transcription of CYP1A1 and the function of the AhR in MCF-7 human breast cancer cells. Quercetin caused a time- and concentration-dependent increase in the amount of CYP1A1 mRNA and CYP1A1 enzyme activity in MCF-7 cells. The increase in CYP1A1 mRNA caused by quercetin was prevented by the transcription inhibitor actinomycin D. Quercetin also caused an increase in the transcription of a chloramphenicol reporter vector containing the CYP1A1 promoter. Quercetin failed to induce CYP1A1 enzyme activity in AhR-deficient MCF-7 cells. Gel retardation studies demonstrated that quercetin activated the ability of the AhR to bind to an oligonucleotide containing the xenobiotic-responsive element (XRE) of the CYP1A1 promoter. These results indicate that quercetin's effect is mediated by the AhR. Kaempferol did not affect CYP1A1 expression by itself but it inhibited the transcription of CYP1A1 induced by the prototypical AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), as measured by a decrease in TCDD-induced CYP1A1 promoter-driven reporter vector activity, and CYP1A1 mRNA in cells. Kaempferol also abolished TCDD-induced XRE binding in a gel-shift assay. Both compounds were able to compete with TCDD for binding to a cytosolic extract of MCF-7 cells. Known ligands of the AhR are, for the most part, man-made compounds such as halogenated and polycyclic aromatic hydrocarbons. These results demonstrate that the dietary flavonols quercetin and kaempferol are natural, dietary ligands of the AhR that exert different effects on CYP1A1 transcription.
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PMID:Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. 1035 56

To determine the molecular mechanisms underlying the "cross talk" between the activity of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), which binds to arylhydrocarbon receptor (AHR) and estradiol (E2)-liganded estrogen receptor (ER), we first examined the initial step of estrogen action, ligand binding to ER. None of the AHR ligands tested, i.e. TCDD, benzo[a]pyrene, 3,3',4,4',5-pentachlorobiphenyl, beta-naphthoflavone, or alpha-naphthoflavone, bound to ER alpha. We report the first examination of TCDD interaction with ER beta: TCDD did not displace E2 from ER beta. We then examined a second possible mechanism, i.e. direct inhibition of ER alpha binding to estrogen response elements (EREs) by the AHR/AHR nuclear translocator (ARNT) complex. The AHR/ARNT heterodimer did not bind either a full or half-site ERE. However, AHR/ARNT bound specifically to oligomers containing naturally occurring EREs derived from the human c-fos, pS2, and progesterone receptor (PR) gene promoters that include xenobiotic response element (XRE)-like sequences. In contrast, neither purified E2-liganded-ER from calf uterus or recombinant human ER alpha bound a consensus XRE. TCDD inhibited E2-activated reporter gene activity from a consensus ERE and from EREs in the pS2, PR, and Fos genes in transiently transfected MCF-7 human breast cancer cells. However, this inhibition was not reciprocal since E2 did not inhibit TCDD-stimulated luciferase activity from the CYP1A1 promoter in transiently transfected MCF-7 or human endometrial carcinoma HEC-1A cells. We propose that at least part of the mechanism by which the AHR/ARNT complex inhibits estrogen action is by competitively inhibiting ER alpha binding to imperfect ERE sites, adjacent to or overlapping XREs.
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PMID:The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. 1061 2

The molecular mechanisms underlying the apparent "cross-talk" between estrogen receptor (ER)- and arylhydrocarbon receptor (AHR)-mediated activities are unknown. To determine how AHR ligand 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may inhibit ER action and, conversely, to examine how 17-beta-estradiol (E(2)) affects AHR activity, we examined discrete activities of each receptor, i.e., protein-protein interactions, DNA binding, and transcriptional activation. We report that AHR interacts directly with ERalpha, COUP-TF, and ERRalpha1, in a ligand-specific manner in vitro. Unoccupied or beta-napthoflavone (beta-NF)-occupied AHR showed stronger interaction with ERalpha, COUP-TF, and ERRalpha1 than when AHR was occupied by the partial antagonist alpha-naphthoflavone (alpha-NF), indicating a role for ligand in AHR interaction with these proteins. We also report that AHR interacts with COUP-TF in transfected CV-1 cells. In contrast, the AHR nuclear translocator protein (ARNT) did not interact with COUP-TF, ERRalpha1, or ERalpha. We next examined the interaction of either ERalpha or COUP-TF with a consensus xenobiotic response element (XRE). Purified ERalpha did not bind the consensus XRE, but COUP-TFI bound the consensus XRE, suggesting a role for COUP-TF as a AHR/ARNT competitor for XRE binding. In transiently transfected MCF-7 human breast cancer cells, overexpression of COUP-TFI inhibited TCDD-activated reporter gene activity from the CYP1A1 promoter. TCDD inhibited estradiol (E(2))-activated reporter gene activity from a consensus ERE and from the EREs in the pS2 and Fos genes, and COUP-TFI did not block the antiestrogenic activity of TCDD. The specific interaction of COUP-TF with XREs and AHR together with the inhibition of TCDD-induced gene expression by COUP-TF suggests that COUP-TF may regulate AHR action both by direct DNA binding competition and through protein-protein interactions.
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PMID:The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. 1062 Mar 35

Recent epidemiologic studies showed increased frequency of birth defects in pesticide applicators and general population of the Red River Valley, Minnesota. These studies further indicated that this crop growing area used more chlorophenoxy herbicides and fungicides than elsewhere in Minnesota. Based on frequency of use and known biology, certain herbicides, pesticide additives, fungicides, and mycotoxins are suspect agents. To define whether these agents affect developmental endpoints in vitro, 16 selected agrochemicals were examined using the MCF-7 breast cancer cell line. In the flow cytometric assay, cell proliferation in this estrogen-responsive cell line indicates xenobiotic-mediated estrogenic effects. Cell viability, morphology, ploidy, and apoptosis were incorporated in this assay. Data showed that the adjuvants X-77 and Activate Plus induced significant cell proliferation at 0.1 and 1 microg/ml. The commercial-grade herbicides 2,4-D LV4 and 2,4-D amine induced cell proliferation at 1 and 10 microg/ml. The reagent-grade 2,4-D products failed to induce proliferation over the same concentration range, suggesting that other ingredients in the commercial products, presumably adjuvants, could be a factor in these results. The fungicides triphenyltin and mancozeb induced apoptosis at concentrations of 4.1 microg/ml (10(-5) M) and 50 microg/ml, respectively. Triphenyltin also induced aneuploidy (C2/M arrest) at 0.41 microg/ml (10(-6) M). Data provide a mechanistic step to understanding human reproductive and developmental effects in populations exposed to these agrochemicals, and initiative to focusing limited resources for future in vivo animal developmental toxicity studies.
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PMID:In vitro studies of cellular and molecular developmental toxicity of adjuvants, herbicides, and fungicides commonly used in Red River Valley, Minnesota. 1093 58

A major goal in molecular epidemiology is to identify preventable environmental risk factors and susceptible subpopulations. In a hospital-based molecular epidemiological case-control study of breast cancer, we investigated the relationship between DNA damage from exposure to polycyclic aromatic hydrocarbons (PAHs) and susceptibility attributable to inherited deletion of the xenobiotic detoxifying gene, glutathione S-transferase M1 (GSTM1). Prior to breast surgery, women (n = 227) were enrolled and interviewed and donated a blood sample. PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples retrieved from pathology blocks, and GSTM1 genotype was determined by PCR using WBC DNA. The GSTM1 analysis included 95 cases and 87 benign breast disease controls. GSTM1 genotype was not associated with breast cancer case-control status (odds ratio = 0.73; 95% confidence interval, 0.37-1.44). However, the GSTM1 null genotype predicted PAH-DNA adduct levels in malignant (beta = 0.407; P = 0.003) and nonmalignant (beta = 0.243; P = 0.05) breast tissue from cases. This relationship was not seen in tissue from controls (beta = 0.095; P = 0.341). When tissue from controls was compared with tumor tissue from cases, there was a significant case-control difference in PAH-DNA adduct levels among women who were GSTM1 null. There was no such case-control difference among women who were homozygous or heterozygous for GSTM1. There was an interaction between GSTM1 and case-control status on adduct levels in breast tissue (P = 0.002). The results suggest that genetic susceptibility to the formation of PAH-DNA adducts in breast tissue may play a role in breast cancer development.
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PMID:The association between glutathione S-transferase M1 genotype and polycyclic aromatic hydrocarbon-DNA adducts in breast tissue. 1104 91

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a basic helix-loop-helix transcription factor that forms heterodimers with the aryl hydrocarbon receptor (AhR) or hypoxia inducible factor-1alpha to activate transcription via xenobiotic response element or hypoxia response element, respectively. Thus, it plays a major role in two key biochemical pathways involved in tumor growth. We previously showed that estrogen receptor (ER)-negative breast cancer cell lines expressed a splice variant of ARNT that was associated with Ah nonresponsiveness. We have now used a sensitive PCR method to analyze the expression of the variant in a series of 92 breast cancers to assess interactions with the ER and prognosis. The splice variant could be detected in all of the cases examined, with high ratios of variant:full-length ARNT (> or =10) characterized in 10 cases. When the patient group was split into quartiles by increasing splice variant ratios, there was an inverse relationship of ER status to ARNT splice-variant ratios (P = 0.01, chi(2)). Univariate analysis showed that cases with high ARNT splice-variant ratios > or =10 had a worse relapse-free and overall survival (P > or = 0.03; hazard ratio, 2.7; and P = 0.006; hazard ratio, 3.9, respectively). In multivariate analysis for relapse-free and overall survival, ARNT splice-variant ratio was the strongest independent factor and, although inversely related to ER, remained a separate risk factor. At least two potential mechanisms could explain this phenomenon: the loss of aryl hydrocarbon receptor-mediated antiestrogenic activity or the blockade of a proapoptotic pathway induced by hypoxia. Because several enzymes involved in drug resistance are induced through a xenobiotic response element, the tumors presenting high ARNT splice-variant ratios may be specifically targeted by drugs normally degraded or inactivated. This study shows the biological importance of ARNT splice variants in the behavior of human breast cancer and suggests that the breast cell lines in which the splice variant was discovered may be useful models for further investigation.
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PMID:Association of ARNT splice variants with estrogen receptor-negative breast cancer, poor induction of vascular endothelial growth factor under hypoxia, and poor prognosis. 1130 28

For the cellular physiology of sex steroid sensitive cells, the androgen/estrogen ratio may be more important than only one hormone action per se, in both sexes. This ratio is controlled in vertebrates by aromatase; its gene expression can be inhibited in different ways, and this is crucial for the treatment of estrogen-dependent diseases such as breast cancer, or gynecomastia in males for instance. To reach this goal, new steroidal and non-steroidal inhibitors are continuously being developed, and some of them are used as first or second line agents. Aromatase inhibition is also an essential tool for studying the role of estrogens in the adult, or during development. Aromatase inhibitors have shown in particular that estrogens are essential also in males for skeletal maturation and bone mineralization, development of masculine dendritic morphology in male brain linked to mating behaviour, and testicular function. Testosterone is often the prohormone converted in situ in active estrogens, at these levels. Several strategies can be used for aromatase inhibition. The first ones employed were blind screening or deductions from in vivo observations, which led for instance to the discovery of the role of aminoglutethimide in aromatase inhibition. Subsequently, in the years 1975-1990, the molecular modeling of compounds to mimic the substrate shape of the enzyme constituted the major idea. Hundreds of chemicals were synthesized by numerous authors, ranging from the well-known and very efficient 4-OHA to complicated imidazole or indane derivatives tested by sophisticated comparative molecular field analyses. Reticulum-bound active aromatase has not as yet been X-ray analyzed. Thus, aromatase inhibitors were also used more recently to probe and understand the active site conformation of the enzyme and its modelization was obtained from comparisons with bacterial-related cytochromes. We developed a mammalian model considerably closer to human aromatase in order to study the active site shape with new potent aromatase non-steroidal inhibitors. This model is equine aromatase. This enzyme was biochemically characterized, purified, and cloned by our group. It allowed testing, by site-directed mutagenesis, predictive hypotheses in human aromatase which contributed to designing of new inhibitors. The understanding of the functioning of an essential member of the cytochrome P450 family, which is necessary for cellular detoxification, was also facilitated. Inhibition of aromatase activity has also been carried out with antibodies directed to the catalytic site and at the gene level by knock-out or by control of factor-specific promoters. This may result in different mRNA synthesized by alternative splicing. We have also obtained specific inhibition of aromatase activity in human cells with antisense stable phosphorothioate oligodeoxynucleotides directed against aromatase mRNA tertiary structures. Besides known steroidal and non-steroidal inhibitors, the antiaromatase effects of compounds found in our daily environment such as dietary flavonoids or xenobiotic pollutants have also been described. Finally, we underline that all these aromatase inhibitors, or methods of aromatase inhibition, can modulate the estrogenic balance essential not only for female, but also for male physiology, including gonadal function.
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PMID:Aromatase inhibitors: past, present and future. 1140 1

Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYPIAI mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5. and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs. responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites. are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.
Breast Cancer Res Treat 2001 Nov
PMID:The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. 1176 4

Women are exposed to xenobiotic estrogens at least to the same extent as men. These estrogenic chemicals are either from plant material in the diet (phytoestrogens) or from industrial sources. Mainly industrially derived environmental estrogens may accumulate within the food chain and persist in human adipose tissue. In contrast, phytoestrogens do not bioaccumulate and are rapidly excreted in urine. The phytoestrogens probably represent the source of most extensive exposure for humans. Epidemiological evidence suggests that diets rich in phytoestrogens are associated with reduced incidences of cardiovascular disease, breast cancer, prostate cancer and osteoporosis. The numerous bioactivities (other than just estrogenicity) of phytoestrogens and related dietary compounds make it difficult to single out the mechanisms mediating such protective effects. The possibility that the newly discovered estrogen receptor beta may be an important modulator of phytoestrogen action is opening up new lines of research. While the evidence suggests that phytoestrogens may be of positive relevance to postmenopausal women, indications that exposure of women to industrially derived xenobiotic estrogens provides risks to health remain unproven. Further work is necessary to clarify the relative importance of 'xenobiotic' estrogens to human health, but it must be emphasized that the estrogenic potency of all the xenobiotic estrogens is very low compared with that of endogenous estrogens.
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PMID:How significant are environmental estrogens to women? 1190 47

Tamoxifen is a widely utilized antiestrogen in the treatment and chemoprevention of breast cancer. Clinical studies document that tamoxifen administration markedly enhances the systemic elimination of other drugs. Additionally, tamoxifen enhances its own clearance following repeated dosing. The mechanisms that underlie these clinically important events remain unresolved. Here, we report that tamoxifen and its metabolite 4-hydroxytamoxifen markedly induce cytochrome P450 3A4, a drug-metabolizing enzyme of central importance, in primary cultures of human hepatocytes. Tamoxifen and 4-hydroxytamoxifen (1-10 microM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6beta-hydroxylation). Maximal induction was achieved at the 5 microM level. At this level, tamoxifen and 4-hydroxytamoxifen caused a 1.5- to 3.3-fold (mean, 2.1-fold) and 3.4- to 17-fold (mean, 7.5-fold) increase in the CYP3A4 activity, respectively. In comparison, rifampicin treatment resulted in a 6- to 16-fold (mean, 10.5-fold) increase. We also observed corresponding increase in the CYP3A4 immunoreactive protein and mRNA levels. Furthermore, tamoxifen and 4-hydroxytamoxifen efficaciously activated the human pregnane X receptor (hPXR; also known as the steroid xenobiotic receptor), a key regulator of CYP3A4 expression. The efficacy of tamoxifen and 4-hydroxytamoxifen relative to rifampicin for hPXR activation was approximately 30 and 60%, respectively. Our results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite. Furthermore, the CYP3A4 induction may be a result of hPXR activation. These findings have important implications for optimizing the use of tamoxifen and in the development of newer antiestrogens.
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PMID:Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen. 1195 Jul 95


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