Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 breast tissue is the site of major metabolic conversions of estradiol (E2) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methytransferase. In addition to E2 itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2-methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E2 and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E2 and its metabolites, and evidence regarding their potential role in breast cancer.
Breast Cancer Res 2004
PMID:Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview. 1553 54

Metastasis, the main reason for high mortality of cancer, is a multistep process. One important step in this process is the adhesion of tumor cells to vascular endothelium at sites distant from primary tumors during hematogenous dissemination. In order to investigate and quantify the adhesion of tumor cells to endothelial cells we developed an in vitro model using MCF-7 breast cancer cells and monolayers of human umbilical vein endothelial cells (HUVEC). The tumor cells were specifically labeled with a fluorescent dye for quantification; for increasing the amount of adherent cells, HUVEC monolayers were stimulated with phorbol ester before the addition of the tumor cells. Due to previous reports that products of several P450 enzymes contribute to the progression of certain kinds of cancer, inhibitors of CYP5 (thromboxane A(2) synthase), CYP17 (17alpha-hydroxylase-C17, 20-lyase), and CYP19 (aromatase) were tested in this in vitro model for their potency to reduce cancer cell adhesion. Within each series of P450 inhibitors, compounds with high inhibitory activity on tumor cell adhesion were identified. At an initial concentration of 100 microM, BW26, a potent inhibitor of CYP5, reduced tumor cell adhesion of MCF-7 to HUVECs to 15%, BW40 (CYP17) to 29%, and SU5a (CYP19) to 11% of the corresponding controls (no inhibitor). Reduction of tumor cell adhesion was shown to occur in a concentration-dependent manner. In addition to these inhibitors of CYP5, CYP17, and CYP19, liarozole, known to be a potent inhibitor of CYP26 (retinoic acid-4-hydroxylase) and ATRA (all-trans-retinoic acid) metabolism, was able to reduce tumor cell adhesion to 51% of the initial rate. Experiments elucidating the mode of action of these compounds revealed that inhibition of the mentioned CYP enzymes is not responsible for their ability to reduce tumor cell adhesion.
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PMID:Discovery of inhibitors of MCF-7 tumor cell adhesion to endothelial cells and investigation on their mode of action. 1559 2

Tamoxifen has been a mainstay of adjuvant therapy for breast cancer for many years. We sought to determine if genetic variability in the tamoxifen metabolic pathway influenced overall survival in breast cancer patients treated with tamoxifen. We examined functional polymorphisms in CYP2D6, the P450 catalyzing the formation of active tamoxifen metabolites, and UGT2B15, a Phase II enzyme facilitating the elimination of active metabolite in a retrospective study of breast cancer patients. We also examined whether the combination of variant alleles in SULT1A1 and UGT2B15 had more of an impact on overall survival in tamoxifen-treated patients than when the genes were examined separately. We conducted a retrospective study using archived paraffin blocks for DNA extraction and data from pathology reports and hospital tumor registry data for information on clinical characteristics, treatment, and outcomes (162 patients receiving tamoxifen and 175 who did not). Genotypes for CYP2D6 and UGT2B15 were obtained and Cox proportional hazards modeling was performed. After adjusting for age, race, stage of disease at diagnosis, and hormone receptor status, we found no significant association between CYP2D6 genotype and overall survival in either group of breast cancer patients. Tamoxifen-treated patients with UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival. When UGT2B15 and SULT1A1 'at-risk' alleles were combined, women with two variant alleles had significantly greater risk of recurrence and poorer survival than those with common alleles. These studies indicate that genetic variation in Phase II conjugating enzymes can influence the efficacy of tamoxifen therapy for breast cancer.
Breast Cancer Res Treat 2005 Jun
PMID:Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. 1595 58

The anti-breast cancer drug tamoxifen that binds to ER is metabolised in human liver by CYP2D6 isoenzyme, whilst the metabolism of 17beta-oestradiol (by hydroxylation) is by phase I biotransformation in the liver to 2-hydroxyoestradiol and to 4-hydroxyoestradiol respectively by two isoenzymes of this mixed function oxidase CYP cytochromes P450 (EC 1.14.14.1); CYP1A2 and by CYP1B1. Nevertheless, it appears that the receptor (AhR) itself causes the expression of oestrogen-regulated target genes (studied by binding of dioxin). This is the result of an unknown signalling mechanism at the genome that is triggered directly by this receptor by binding promiscuously to ER (alpha or beta) sites. This has been observed even in the absence of oestrogens or mimics therefore in genome-binding investigations of target tissues such as uterus: oestrogen-receptor (ER) is likely to be promiscuous therefore. Furthermore, AhR (polycyclic aromatic hydrocarbon receptor), when activated by the binding of aromatic hydrocarbons (Ah) forms a complex with the aryl hydrocarbon nuclear-translocator chaperone protein (Arnt). It is this binding to xenobiotic response elements in DNA that initiates expression of the appropriate oestrogen-regulated target-genes in the uterus and other target tissues (including mammary, ovaries, and brain). The likely promiscuity of oestrogen receptors is proposed to be the cause of numerous side effects when oestrogen is involved in therapy, these can be manifest in hormone replacement therapy (HRT) and in the incorporation of synthetic oestrogens in the wide varieties of oral contraceptives now available.
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PMID:Oestrogen-receptors (ER) are likely to be promiscuous: wider role for oestrogens and mimics. 1596 Dec 52

Tamoxifen (TAM), used as the endocrine therapy of choice for breast cancer, undergoes metabolism primarily forming N-desmethyltamoxifen, 4-hydroxytamoxifen, alpha-hydroxytamoxifen, and tamoxifen-N-oxide (TNO). Our earlier studies demonstrated that flavin-containing monooxygenases (FMOs) catalyze the formation of TNO. The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM. CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 all reduced TNO, with CYP2A6, CYP1A1, and CYP3A4 producing the greatest reduction. A portion of TAM formed by CYP3A4-mediated reduction of TNO was further metabolized, but not TAM formed by the other P450s. TNO reduction by P450s is extremely rapid with considerable TAM formation detected at the earliest time point that products could be measured. TAM formation exhibited a lack of linearity with incubation time but increased linearly as a function of TNO and P450 concentration. TNO was converted into TAM by reduced hemoglobin (Hb) and NADPH-P450 oxidoreductase, suggesting involvement of the same heme-Fe(2+) complex in both Hb and P450s. The findings raise the question of whether the reductive activity may be nonenzymatic. Results of this in vitro study demonstrate the potential of TAM and TNO to be interconverted metabolically. FMO seems to be the major enzymatic oxidant, whereas several P450 enzymes and even reduced hemoglobin are capable of reducing TNO back to TAM. The possibility that these processes may comprise a metabolic cycle in vivo is discussed in this article.
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PMID:Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. 1598 77

Cancers, including that of the breast, are the result of multiple contributing factors including aberrant gene expression. Indeed, the CYP19 gene encoding P450 aromatase, the key enzyme for estrogen biosynthesis, is up-regulated in breast tumors predominantly via the cAMP-responsive gonad-type PII promoter, ultimately leading to increased intratumoral estrogen production and tumor growth. Thus, identifying the molecular factors involved in aromatase PII promoter regulation is essential for our understanding and treatment of the disease. Because we have previously shown activity of the murine aromatase PII promoter to be markedly up-regulated by GATA factors with respect to the gonads, we hypothesized that GATA factors are also key determinants of human PII promoter-driven aromatase transcription in breast tumors. We now show that GATA3 and GATA4 are indeed expressed in several breast cancer cells lines. Consistent with the cAMP dependence of the PII promoter, activation elicited by GATA3 or GATA4 alone and the striking synergism between GATA3 or GATA4 and the nuclear receptor liver receptor homolog (LRH)-1 was intimately linked to forskolin treatment or overexpression of protein kinase A (PKA) catalytic subunit. PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. Finally, we show that the human LRH-1 promoter is itself a target for GATA factors. Thus, taken together, our results suggest that GATA factors likely contribute to aberrant aromatase expression in breast tumors through two distinct, yet complementary mechanisms.
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PMID:Protein kinase A-dependent synergism between GATA factors and the nuclear receptor, liver receptor homolog-1, regulates human aromatase (CYP19) PII promoter activity in breast cancer cells. 1610 88

Gene therapy using the prodrug-activating enzyme P450 2B6 has shown substantial promise in preclinical and initial clinical studies with the P450 prodrugs cyclophosphamide and ifosfamide. We sought to optimize this therapy using the canine P450 enzyme 2B11, which activates cyclophosphamide and ifosfamide with Km of 80 to 160 micromol/L, approximately 10- to 20-fold lower than the Km of P450 2B6. Retrovirus encoding a P450 2B11-internal ribosome entry signal-P450 reductase expression cassette induced marked cyclophosphamide and ifosfamide cytotoxicity toward 9L gliosarcoma cells and exhibited an impressive bystander killing effect at micromolar prodrug concentrations, where P450 2B6 displayed low activity. Adeno-2B11, a replication-defective, E1/E3 region-deleted adenovirus engineered to coexpress P450 2B11 and P450 reductase, dramatically increased tumor cell-catalyzed cyclophosphamide 4-hydroxylation and cytotoxicity compared with Adeno-2B6 and effected strong bystander killing at low (20 micromol/L) cyclophosphamide concentrations. Further increases in cyclophosphamide cytotoxicity were obtained in several human cancer cell lines, including a 4-hydroperoxycyclophosphamide-resistant MCF-7 breast cancer cell line, when Adeno-2B11 was combined with Onyx-017, an E1b-55-kDa gene-deleted, tumor cell-replicating adenovirus that coamplifies and facilitates tumor cell spread of Adeno-2B11. To evaluate the therapeutic effect of P450 2B11 expression in vivo, 9L gliosarcoma cells transduced with P450-expressing retrovirus were grown as solid s.c. tumors in immunodeficient mice. Cyclophosphamide treatment on a metronomic, 6-day repeating schedule led to full regression of 9L/2B11 tumors but not P450-deficient control tumors, resulting in a tumor-free period lasting up to approximately 100 days. 9L/2B6 tumors regressed more slowly and exhibited a tumor-free period of only 21 to 39 days. Thus, P450 gene-directed enzyme prodrug therapy can be greatly improved by using the low Km P450 enzyme 2B11, which catalyzes intratumoral activation of cyclophosphamide and ifosfamide at pharmacologically relevant drug concentrations.
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PMID:Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. 1654 68

David Kupfer's research career spanned 50 years and he authored or co-authored over 160 papers and book chapters. Although best known for his work centering on cytochrome P450 metabolism of prostaglandins, steroids, and proestrogenic compounds, David's research also contributed key advances in the areas of P450 induction and catalytic mechanism, breast cancer therapy, and analytical methodology. His research is reviewed here.
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PMID:David Kupfer: a career retrospective. 1668 44

Cytochrome P450 19 (P450 19, aromatase) constitutes a successful target for the treatment of breast cancer. This study analyzes chemical features common to P450 19 inhibitors to develop ligand-based, selective pharmacophore models for this enzyme. The HipHop and HypoRefine algorithms implemented in the Catalyst software package were employed to create both common feature and quantitative models. The common feature model for P450 19 includes two ring aromatic features in its core and two hydrogen bond acceptors at the ends. The models were used as database search queries to identify active compounds from the NCI database.
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PMID:Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors. 1671 49

P450 (CYP) and glutathione S-transferase (GST) are involved in the activation and detoxification of many potential carcinogens. Although, the interaction between environmental exposure and genetic polymorphisms of cytochrome P450 2E1 (CYP2E1) and glutathione S-transferase M1 (GSTM1) in breast cancer has been assessed, the gene-gene interactions between CYP2E1 and GSTM1 related to breast cancer have not been focused on and reported. We conducted a hospital-based case-control study to investigate whether the genetic interaction effects of CYP2E1 and GSTM1 modify the risk of developing breast cancer independent of the effect of cigarette smoking and alcohol consumption. Individuals with the C2/C2 genotype of CYP2E1 had a lower risk (OR = 0.24, 95% CI = 0.08-0.74) when compared with those with the C1/C1 genotype. However, there was no significant difference (OR = 1.05, 95% CI = 0.73-1.50) in the GSTM1 genotype frequency between the cases with breast cancer and that of the controls. When individuals with the genotype of C1/C1 or C1/C2 of CYP2E1 and the wild-type of GSTM1 were compared with those of C2/C2 of CYP2E1 and the null-type of GSTM1 however, we found a significantly increased risk (OR = 3.50, 95% CI = 1.01-16.55) in the breast cancer patients. Our findings indicated a gene-gene interaction between CYP2E1 and GSTM1 was accessible to developing breast cancer in Taiwanese women without the habits of cigarette smoking and alcohol consumption even though independent effects of CYP2E1 and GSTM1 were weak or non-significant and suggest that environmental carcinogen besides cigarette and alcohol consumption could induce breast cancer.
Breast Cancer Res Treat 2006 Nov
PMID:Interaction of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferase M1 to breast cancer in Taiwanese woman without smoking and drinking habits. 1675 19


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