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)

Epidemiological studies indicate that Asian women have a lower breast cancer incidence compared with their counterparts in the West, and the difference has been related to soya consumption. Animal studies have suggested that soya may prevent dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in the breast. In the present study a cell culture model was developed to address the effect of soya isoflavones on the DMBA-induced DNA damage. DMBA is metabolized into a DNA-attacking moiety by two phase I cytochrome P450 (CYP) enzymes CYP1A1 and CYP1B1. DNA mutation caused by this genotoxic agent is a crucial step in cancer initiation. Substances that interfere with the CYP1 enzyme activities can affect the initiation. In the present study, genistein was found to be an effective inhibitor of recombinant human CYP1A1 and CYP1B1 with Ki of 15.35 and 0.68 micromol/l. The other soya isoflavone daidzein, on the other hand, did not demonstrate any significant inhibition of the enzyme activities. At the transcriptional level, DMBA induced the CYP1 enzyme expressions by stimulating the xenobiotic response element (XRE)-dependent transactivation pathway. When genistein (25 micromol/l) was co-administered with DMBA, the XRE-Luc activity the CYP1 mRNA abundances were significantly suppressed. The present study illustrated that the soya isoflavone genistein, but not daidzein, protected against DMBA genotoxicity.
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PMID:A potential protective mechanism of soya isoflavones against 7,12-dimethylbenz[a]anthracene tumour initiation. 1290 8

Cytochrome P450 (CYP)1A1 and CYP1B1, which are under the regulatory control of the aryl hydrocarbon (Ah) receptor (AhR), catalyze the metabolic activation of numerous procarcinogens and the hydroxylation of 17beta-estradiol (E2) at the C-2 and C-4 positions, respectively. There is evidence of cross-talk between estrogen receptor alpha (ERalpha)- and AhR-mediated signaling in breast and endometrial cells. To further examine these interactions, we investigated the short- and long-term effects of E2 exposure on Ah responsiveness in MCF-7 human breast cancer cells. Short-term exposure to 1 nM E2 elevated the ratio of the 4- to 2-hydroxylation pathways of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced E2 metabolism and the ratio of the induced CYP1B1 to CYP1A1 mRNA levels, as determined by real-time PCR. Cells maintained long-term (9-12 months) in low-E2 medium progressively lost Ah responsiveness, as indicated by diminished rates of TCDD-induced E2 metabolism and ethoxyresorufin O-deethylase activity, and the reduced expression of the CYP1A1 and CYP1B1 mRNAs and proteins levels. These E2-deprived cells showed elevated levels of ERalpha mRNA, depressed levels of AhR mRNA, and unchanged levels of the AhR nuclear translocator mRNA. Transient transfection studies using a CYP1B1-promoter-luciferase reporter construct showed that reduced CYP1B1 promoter activity in E2-deprived cells could be restored by co-transfection with an AhR expression construct, indicating that AhR expression was limiting in these cells. The reduced Ah responsiveness of E2-deprived cells was reversed by culture for four passages in medium supplemented with 1 nM E2; ERalpha and AhR mRNAs returned to near-normal levels and the inducibility of the CYP1A1 and CYP1B1 mRNAs, proteins, and E2 metabolic activities by TCDD was restored. These studies indicate that the continued presence of estrogen is required to maintain high levels of AhR expression and inducibility of the procarcinogen-bioactivating enzymes, CYP1A1 and CYP1B1, in MCF-7 cells.
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PMID:Estrogen regulates Ah responsiveness in MCF-7 breast cancer cells. 1297 67

2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), the most abundant heterocyclic amine (HCA) in cooked food, is a mammary carcinogen in female rats. In humans, consumption of well-done meat and PhIP intake have been associated with an increased risk of breast cancer, but PhIP-DNA adducts have not been analyzed in breast tissues from women having unknown exposure to HCAs. Using an immunohistochemistry (IHC) method, we measured PhIP-DNA adducts in normal breast tissues of 106 women having newly diagnosed breast cancer in comparison with those of 49 women undergoing reduction mammoplasty. The IHC method was first validated in MCF-7 cells treated with different doses of N-hydroxy-PhIP. We detected significant dose-response relationship and correlation (r=0.94) between the levels of PhIP-DNA adducts detected by IHC and 32P-postlabeling. Using IHC, PhIP-DNA adducts were detected in 82 and 71% of the normal breast tissue sections from the cancer and control patients respectively. The median (range) absorbance was 0.18 (0-0.57) and 0.08 (0-0.38) in the cancer and control patients, respectively (P<0.001). Using the median in the controls as a cutoff point, 71% of the cancer patients and 47% of the controls were distributed in the higher range (chi2=8.17; P=0.004). Logistic regression analysis demonstrated an OR of 4.03 (95% CI, 1.41-11.53) after adjusting for age and ethnicity (P=0.009). Stratified analyses did not find any significant effect of age, ethnicity, smoking, well-done meat consumption, dietary intake of PhIP, or polymorphisms of CYP1A1, CYP1B1, NAT2, and GSTM1 genes on the level of PhIP-DNA adducts. However, a potential interactive effect of well-done meat consumption and NAT2 genotype on the level of PhIP-DNA adducts was observed (P=0.047). This is the first study of detection of PhIP-DNA adducts in breast tissue samples obtained from women having unknown exposure to HCAs. These data strongly support the hypothesis that HCA exposure contributes to human breast cancer among genetically susceptible individuals.
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PMID:Detection of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine-DNA adducts in normal breast tissues and risk of breast cancer. 1450 91

Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative breast cancers. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42-1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen.
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PMID:Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk. 1460 39

The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. Several studies suggest that endogenous AhR ligand(s) may exist. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1, as measured by estradiol and ethoxyresorufin metabolism, and on induction of the CYP1A1 and CYP1B1 mRNAs. With 4-hr exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6-9 hr post-exposure and had disappeared by 24 hr, whereas TCDD-induced activities remained elevated for at least 72 hr. The effects of indirubin on CYP mRNA induction were maximal at 3 hr. Indirubin was metabolized by microsomes containing cDNA-expressed human CYP1A1 or CYP1B1. The potency of indirubin was comparable to that of TCDD in a CYP1B1-promoter-driven luciferase assay, when MCF-7 cells were co-exposed to the AhR ligands together with the CYP inhibitor, ellipticine. Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism.
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PMID:Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. 1463 89

Recent success of chemoprevention with tamoxifen has opened a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer. Since tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive, but not ER-negative, breast cancer in the chemoprevention trial (P-1), it seems to be important to develop risk factors for ER-positive breast cancer in order to select the candidates for chemoprevention more appropriately. Estrogens, the major risk factors for breast cancer, are speculated to affect breast cancer risk through ER, thus, genetic polymorphisms of the genes involved in the estrogens biosynthesis and metabolism are expected as risk factors for ER-positive breast cancer. Significance of polymorphisms of the genes involved in estrogens biosynthesis (CYP17, CYP19) and metabolism (CYP1A1, CYP1B1, COMT) in modulating the susceptibility to breast cancer is reviewed. The ethnic difference of the variant allele frequencies between Caucasian women and Asian women is also discussed.
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PMID:Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. 1463 91

Some PCB congeners have shown oestrogenic effects, and this has raised concern that they may increase the risk of breast cancer. In this article we provide a quantitative review of the epidemiologic evidence on environmental exposure to PCBs and breast cancer risk. The vast majority of prospective and retrospective studies did not find any association between total PCB concentrations and breast cancer risk. No association was found for congeners in groups I (potentially oestrogenic) and III (biologically persistent phenobarbital-type cytochrome P450 inducers), according to the classification proposed by Wolff and Toniolo, while less consistent results were reported for group II (potentially anti-oestrogenic and immunotoxic, dioxin-like). Two studies found a threefold risk of postmenopausal breast cancer for women with an A2455G base change in exon 7 of the polymorphic CYP1A1 gene (a member of the cytochrome P450 family) and high PCB levels, compared with women with two wild-type alleles and low PCB, based however on very few cases. Thus, the epidemiological evidence does not support the hypothesis of an association of environmental exposure to PCBs in adulthood in the general population and risk of breast cancer, although uncertainties remain for selected subgroups of women or individual PCB congeners.
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PMID:Environmental exposure to polychlorinated biphenyls (PCBs) and breast cancer: a systematic review of the epidemiological evidence. 1463 29

Several known anti-cancer agents have been shown to lead to increased expression of phase 2 metabolic enzymes without affecting phase 1 enzymes. Phase 1 cytochrome P450 (CYP) enzymes are relevant in cancer studies in that they are involved in oxidative metabolism, biotransformation and detoxification, whereas phase 2 enzyme catalysis leads to clearance. In this study, we obtained semi-quantitative measurements of cytochrome P450 (phase 1) and phase 2 microsomal epoxide hydrolase (mEH) gene expression levels in response to treatment of MCF-7 breast cancer cells with water-soluble Vernonia amygdalina (V.A.) extract. V.A., a vegetable grown in Nigeria, has potential as an anti-cancer agent. The results of Western blot and RT-PCR analyses show that V.A. extract acts as a monofunctional inducer within exposure times ranging from 2-16 hr and dose ranges from 3-100 microg/ml of V.A. Exposure of cells to low doses of V.A. did not affect expression levels of CYP1A1/1A2 mRNA, but lead to induction of mEH, thus supporting the chemotherapeutic potential of VA. However, in parallel studies, CYP3A4 gene expression was also induced, suggesting potential intermediates which influence drug-drug interactions. These data are useful toward further validating V.A. extract as a potential clinically useful natural anti-cancer agent and provide some support for the concept that modulation in CYP3A4 expression in response to treatment is relevant to prognosis.
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PMID:Time and dose-dependent modulation of phase 1 and phase 2 gene expression in response to treatment of MCF-7 cells with a natural anti-cancer agent. 1468 87

A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluoro-benzothiazole (5F-203), like its non-fluorinated parent compound (DF-203), has a unique cytotoxicity pattern in the National Cancer Institute in vitro anticancer drug screen. These compounds show selective toxicity for a subset of cell types including estrogen receptor positive breast cancer and certain renal and ovarian cancer cell lines. Metabolic activation of these benzothiazoles seems to be mediated through the CYP1 family of cytochrome P450s. In an effort to characterize the involvement of CYP1A1 and CYP1B1 in the unique toxicity response of 5F-203, constitutive and 5F-203-induced gene expression patterns were measured in 60 cell lines of the National Cancer Institute drug screen using TaqMan real-time PCR. The patterns of CYP1A1 and CYP1B1 gene expression in the 60 cell lines were correlated with the toxicity pattern of 5F-203 and DF-203. There was significant correlation between drug sensitivity and induced CYP1A1 (R = 0.752, P < 0.001), but not constitutive CYP1A1 mRNA expression. CYP1A1 protein expression was found to mirror the corresponding gene expression, indicating that gene expression changes were concordant with function. Treatment of sensitive cell lines with 10 micro M resveratrol, an inhibitor of CYP1A1 induction, in combination with either 1 or 10 micro M 5F-203 showed an ablation of the observed CYP1A1, but not CYP1B1 mRNA induction in parallel with a decreased sensitivity to 5F-203. Fine needle aspirates were obtained from a variety of human tumor xenografts, and treated ex vivo with 1 micro M 5F-203 for 24 h. In these samples, induction of CYP1A1 by 5F-203 correlated with in vitro sensitivity (R = 0.711, P < 0.05), and corresponded to in vivo sensitivity in human tumor xenografts. These data are concordant with the idea that toxicity of 5F-203 requires activation by CYP1A1, and therefore induction of CYP1A1 mRNA in response to 5F-203 treatments ex vivo may provide a possible surrogate marker for determination of drug-sensitive tumors in patients.
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PMID:Induction of CYP1A1 in tumor cells by the antitumor agent 2-[4-amino-3-methylphenyl]-5-fluoro-benzothiazole: a potential surrogate marker for patient sensitivity. 1470 67

LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR(3)). Ten nanomolar dihydrotestosterone (DHT) and 17 beta-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR(3); however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.
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PMID:Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation. 1502 81


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