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)

Glutathione S-transferases (GSTs), a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents, can be separated by biochemical and immunologic characteristics into three distinct classes named alpha, mu, and pi. Previous studies have indicated that there is marked heterogeneity in the expression of different GST isoenzymes in different normal and malignant tissues. To better understand the regulation of the human pi class glutathione S-transferase isoenzyme (GST-pi), the tissue distribution of this protein wa studied by an immunohistochemical technique using an anti-GST-pi polyclonal antibody in normal paraffin-embedded human tissues. These studies indicate that there is a broad distribution of GST-pi in normal human tissues and establish a precise localization within the different organs studied. GST-pi was expressed predominantly in normal epithelial cells of the urinary, digestive, and respiratory tracts, suggesting a possible role for GST-pi in detoxication and elimination of toxic substances. Previous studies have indicated that GST-pi and the putative drug efflux pump P-glycoprotein are both overexpressed in multidrug-resistant human breast cancer cells and in xenobiotic resistant preneoplastic rat hyperplastic liver nodules. Results from this study indicate that there are also similarities between the normal tissue distribution GST-pi and that previously reported for mammalian P-glycoprotein, particularly in secretory epithelia. This finding suggests that these two gene products, which have been implicated in the development of resistance to cytotoxic drugs, may be coregulated in normal and malignant cells.
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PMID:An immunohistochemical study of pi class glutathione S-transferase expression in normal human tissue. 197 19

We investigated the expression of the genes for several antioxidant and xenobiotic-detoxifying enzymes in the multidrug-resistant variant of the human breast cancer cell line MCF-7, MCF-7/Dox. MCF-7/Dox is greater than 500-fold resistant to doxorubicin by clonogenic assay. Enzyme activity determinations in the cytoplasmic compartment of MCF-7/Dox revealed a 25-fold increase in glutathione peroxidase level compared to the parent line (mean +/- SD, 10 +/- 2.8 versus 0.4 +/- 0.24 nmol/min/mg; P less than 0.005). The activity of the other major hydrogen peroxide-detoxifying enzyme, catalase, was diminished in MCF-7/Dox (2.0 +/- 0.4 versus 4.8 +/- 1.4 mumol/min/mg; P less than 0.025 compared to MCF-7). Superoxide dismutase activity did not differ between the two cell lines. The specific activity of the xenobiotic-detoxifying enzyme DT-diaphorase was 4-fold lower in MCF-7/Dox compared to MCF-7 (DT-diaphorase, 117 +/- 45 versus 509 +/- 123 nmol/min/mg; P less than 0.005). Daunorubicinol-producing carbonyl reductase activity was equal in the two lines. Northern blot analysis demonstrated a 0.9-kilobase band of glutathione peroxidase mRNA in MCF-7/Dox; no glutathione peroxidase mRNA was detected in MCF-7. A 2.4-kilobase catalase and 0.7- and 1.4-kilobase superoxide dismutase mRNAs were detectable in MCF-7/Dox and MCF-7. When normalized to 28S RNA, no difference in the mRNA levels of catalase and superoxide dismutase in MCF-7/Dox and MCF-7 could be determined. DT-diaphorase mRNAs of 1.4 and 2.7 kilobases were found in both MCF-7/Dox and MCF-7 cells. A 1.2-kilobase mRNA homologous to the putative carbonyl reductase cDNA was also easily detectable in both MCF-7 and MCF-7/Dox. The amount of mRNA for both xenobiotic-detoxifying enzymes was decreased 2- to 4-fold in the doxorubicin-resistant cells. Southern blot analysis of PstI- and MspI-restricted genomic DNA revealed no evidence for amplification or rearrangement of the glutathione peroxidase gene. These results indicate that, in addition to the previously described overexpression of anionic glutathione S-transferase in MCF-7/Dox cells, an augmented glutathione peroxidase mRNA level is the major alteration in antioxidant and xenobiotic-detoxifying enzyme expression that could contribute to doxorubicin insensitivity in these multidrug-resistant breast cancer cells.
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PMID:Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant MCF-7 breast cancer cells. 240 12

In order to compare the interactions of procarcinogens with mammary cells from humans and rats, a uniform set of mediated mutagenesis assays has been established. In these assays, species-specific mammary epithelial cells activate procarcinogens, and specific locus mutations are quantitated in cocultured V-79 cells. Mutations were induced in the rat mammary cell coculture system exposed to 7,12-dimethylbenz(a)anthracene but not benzo(a)pyrene. In contrast, in the human mammary cell coculture system benzo(a)pyrene was much more effective than 7,12-dimethylbenz(a)anthracene in the induction of mutations. These results suggest caution in extrapolating carcinogenesis data between rodents and humans. They also suggest that the relationship between the ubiquitous environmental xenobiotic benzo(a)pyrene and the etiology of human breast cancer requires further exploration.
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PMID:Interspecies comparison of human and rat mammary epithelial cell-mediated mutagenesis by polycyclic aromatic hydrocarbons. 242 69

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.
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PMID:Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas. 289 Jan 68

The aryl hydrocarbon (Ah) receptor binds several different structural classes of chemicals, including halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic and heteropolynuclear aromatic hydrocarbons. TCDD induces expression of several genes including CYP1A1, and molecular biology studies show that the Ah receptor acts as a nuclear ligand-induced transcription factor that interacts with xenobiotic or dioxin responsive elements located in 5'-flanking regions of responsive genes. TCDD also elicits diverse toxic effects, modulates endocrine pathways and inhibits a broad spectrum of estrogen (17 beta-estradiol)-induced responses in rodents and human breast cancer cell lines. Molecular biology studies show that TCDD inhibited 17 beta-estradiol-induced cathepsin D gene expression by targeted interaction of the nuclear Ah receptor with imperfect dioxin responsive elements strategically located within the estrogen receptor-Sp1 enhancer sequence of this gene.
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PMID:Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. 749 65

The nonsteroidal antiestrogen tamoxifen is widely used in breast cancer treatment and is currently under evaluation as a chemopreventive agent for individuals at high risk of contracting the disease. The effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in F344 rat liver have been investigated. Tamoxifen administration for 7 days produced a dose-dependent increase in enzyme expression similar to that reported to be produced by phenobarbital. Increases in CYPIIB1, CYPIIB2, CYPIIIA, and microsomal epoxide hydrolase mRNA and protein levels in males and females were observed by Western and Northern blotting. The expression of CYPIA1, CYPIA2, and gamma-glutamyl transpeptidase mRNA was not significantly affected by tamoxifen treatment. Tamoxifen was approximately one-tenth as potent an inducer of combined CYPIIB1/2 mRNA compared with phenobarbital when the two drugs were administered at equimolar doses. In addition to the effects observed after short-term tamoxifen exposure, increases in CYPIIB1 and CYPIIB2 protein levels were noted after 6 and 15 months of 250 ppm tamoxifen in the diet. Taken together, these results suggest that tamoxifen is a weak phenobarbital-like inducer. However, there are significant differences in the induction profiles produced by the two drugs. Most significant of these differences was the relatively weak induction of CYPIIB1 but striking induction of CYPIIB2 by tamoxifen. In addition, females were often more sensitive than males to tamoxifen, especially at low doses. These differences suggest that tamoxifen and phenobarbital do not use identical molecular mechanisms to produce enzyme induction. It is possible that the effects of tamoxifen are a result of phenobarbital-like properties coupled with the effects of tamoxifen-induced hormonal perturbations in the animal. In sum, tamoxifen induces enzyme expression in rats at a dose comparable, on a mg/kg basis, to the dose women receive for disease management, suggesting these results may be significant for human exposure.
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PMID:Effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in rat liver. 771 88

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit diverse toxic and biochemical responses in laboratory animals and mammalian cells in culture. TCDD induces CYP1A1 gene expression and results of extensive research have delineated the molecular mechanism of this response. In target cells, TCDD initially binds to the aryl hydrocarbon (Ah) receptor which accumulates in the nucleus as an Ah-receptor:aryl hydrocarbon nuclear translocator (Arnt) protein heterodimeric complex. The nuclear Ah receptor complex acts as a ligand-induced transcription factor which binds to transacting genomic dioxin/xenobiotic responsive elements (DREs/XREs) located in the 5'-regulatory region upstream from the initiation start site and this interaction results in transactivation of gene transcription. DREs have been identified in several other genes which are induced by TCDD, including CYP1A2, aldehyde-3-dehydrogenase, NAD(P)H quinone oxidoreductase, and glutathione S transferase Ya and similar induction response pathways have been observed or proposed. However, TCDD and other Ah receptor agonists also inhibit expression of several genes and research in this laboratory has investigated inhibition of estrogen (E2)-induced genes including uterine epidermal growth factor, c-fos protooncogene, and the progesterone receptor, estrogen receptor (ER) and cathepsin D genes in human breast cancer cell lines. In MCF-7 human breast cancer cells, E2 induces cathepsin D gene expression and this is associated with formation of an ER/Sp1 complex at the sequence in the promoter region (-199/-165) of this gene. Within 30 min TCDD causes a rapid inhibition of E2-induced cathepsin D gene expression in MCF-7 cells. Moreover, using a series of synthetic oligonucleotides which include the wild-type ER/Sp1 and various mutants, it was shown by gel electromobility shift and transient transfection assays that the nuclear Ah receptor complex binds to an imperfect DRE located between the ER and Sp1 binding sequences. This interaction results in disruption of the ER/Sp1 complex and inhibition of E2-induced gene expression. These results illustrate that the nuclear Ah receptor complex also exhibits activity as a negative transcription factor via a mechanism which is similar to that reported for Ah receptor-mediated induction of gene expression.
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PMID:Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. 778 96

We have studied the expression of different xenobiotic metabolizing enzymes in primary operable breast cancer of no special type. The expression of two forms of cytochrome P450, microsomal epoxide hydrolase, and three classes of glutathione S-transferase was investigated using immunohistochemistry. The tumours were characterized by consistent expression of microsomal epoxide hydrolase and by variable expression of the two forms of cytochrome P450 and the three types of glutathione S-transferase. Cytochrome P450 1A and cytochrome P450 3A were identified in 39 and 22 per cent of tumours, respectively. In each case, immunostaining was present only in areas of invasive carcinoma. Epoxide hydrolase was identified in 89 per cent of tumours and glutathione S-transferases pi, mu, and alpha were identified in 56, 65, and 44 per cent of tumours, respectively. Immunoreactivity for epoxide hydrolase and glutathione S-transferases was identified in both tumours and non-neoplastic breast tissue. The presence of different xenobiotic metabolizing enzymes may have a role in determining the intrinsic drug resistance of breast cancer to a variety of anti-cancer drugs, and the expression of these enzymes can readily be assessed using immunohistochemistry.
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PMID:Expression of xenobiotic metabolizing enzymes in breast cancer. 849 28

17 beta-Estradiol (E2) induces cathepsin D mRNA levels and intracellular levels of immunoreactive protein in MCF-7 human breast cancer cells. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alone does not affect cathepsin D gene expression in this cell line; however, in cells cotreated with TCDD and E2, TCDD inhibited E2-induced cathepsin D mRNA levels, the rate of gene transcription, and levels of immunoreactive protein. The inhibitory responses were observed within 30 to 120 min after the cells were treated with TCDD. TCDD also inhibited E2-induced secreted alkaline phosphatase activity in aryl hydrocarbon (Ah)-responsive MCF-7 and wild-type mouse Hepa 1c1c7 cells cotransfected with the human estrogen receptor (hER) and the pBC12/S1/pac plasmid, which contains the 5' promoter region (-296/+57) of the cathepsin D gene and an alkaline phosphatase reporter gene. The E2-responsive ER/Sp1 sequence (-199 to -165) in the cathepsin D 5' region contains an imperfect GTGCGTG (-175/-181) xenobiotic responsive element (XRE); the role of this sequence in Ah responsiveness was investigated in gel electrophoretic mobility shift assays and with plasmid constructs containing a wild-type ER/Sp1 oligonucleotide or a mutant ER/Sp1-"XRE" oligonucleotide containing two C-->A mutations in the XRE sequence (antisense strand). In plasmid constructs which contained a chloramphenicol acetyltransferase reporter gene and the wild-type ER/Sp1 promoter sequence, E2-induced chloramphenicol acetyltransferase activity and mRNA levels were inhibited by TCDD whereas no inhibition was observed with the mutant ER/Sp1-"XRE" plasmids. Electrophoretic mobility shift assays showed that the nuclear or transformed cytosolic Ah receptor complex blocked formation of the ER-Sp1 complex with the wild-type but not the ER/Sp1 mutant oligonucleotide. Moreover, incubation of the wild-type bromodeoxyuridine-substituted ER/Sp1 oligonucleotide with the nuclear Ah receptor complex gave a specifically bound cross-linked 200-kDa band. These data demonstrate that Ah receptor-mediated inhibition of E2-induced cathepsin D gene expression is due to disruption of the ER-Sp1 complex by targeted interaction with an overlapping XRE.
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PMID:Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. 852 36

Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular glutathione increases toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation using the drug buthionine sulfoximine. The fact that some drug-resistant cell lines have increased GSH levels, and that enhancing glutathione concentrations in animal tissues protects against a variety of xenobiotic agents, suggests a different potential approach to improve anticancer therapy. We previously showed a selective enhancement by the cysteine "pro-drug," L-2-oxothiazolidine-4-carboxylate (OTZ), of GSH concentration in some normal tissues of tumor-bearing rats, whereas there is a paradoxic GSH depletion in tumor. OTZ has been shown to protect animals from a variety of toxins, and in vitro studies showed a selective increase in GSH in normal cells that results in reduced sensitivity to some chemotherapy drugs. This report describes evidence that OTZ provides this effect in an in vivo rat mammary tumor model. We have examined the OTZ "activating" enzyme, 5-oxoprolinase, in these tumors and found it to be 4-fold lower than that of normal rat liver. This may explain at least the lack of increased GSH in tumor in response to OTZ. A limited number of human breast cancer samples show similar activity.
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PMID:Modulation of glutathione by a cysteine pro-drug enhances in vivo tumor response. 878 49


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