UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of CYP1B1 has been identified in breast cancer using the reverse transcriptase-polymerase chain reaction and immunoblotting. CYP1B1 mRNA was expressed in the majority of breast tumours and immunoblotting of breast tumours identified a single protein band of molecular weight 60 kDa corresponding to the predicted molecular weight of human CYP1B1. This is the first study to identify CYP1B1 expression in a tumour where it may represent a previously unknown pathway for the metabolism of oestradiol and chemotherapeutic drugs.
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PMID:Expression of cytochrome P450 CYP1B1 in breast cancer. 758 51

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

Rates of microsomal 17 beta-estradiol (E2) hydroxylation at the C-2, -4, -6 alpha, and -15 alpha positions are each induced greater than 10-fold by treating MCF-7 breast cancer cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The TCDD-induced activities at the C-2, -6 alpha and -15 alpha positions have been attributed to cytochrome P450 1A1 (CYP1A1); however, the low Km 4-hydroxylase induced by TCDD appears to be a distinct enzyme. We report here that antibodies to cytochrome P450-EF (mouse CYP1B1) selectivity inhibited the C-4 hydroxylation of E2 catalyzed by microsomes from TCDD-treated MCF-7 cells. Western blots probed with anti-CYP1B antibodies showed the induction of a 52 kDa microsomal protein in response to treatment with TCDD in MCF-7 cells. Western blots of microsomes from HepG2 cells did not show the TCDD-induced 52 kDa protein, and microsomes from TCDD-treated HepG2 cells did not catalyze a low Km hydroxylation of E2 at C-4. Cellular metabolism experiments also showed induction of both the C-2 and -4 hydroxylation pathways in TCDD-treated MCF-7 cells as evidenced by elevated 2- and 4-methoxyestradiol (MeOE2) formation. In contrast, TCDD-treated HepG2 cells showed 2-MeOE2 formation predominantly over 4-MeOE2. Northern blots of RNA isolated from untreated and TCDD-treated cells, when probed with the human CYP1B1 cDNA, showed induction of a 5.2 kb RNA in MCF-7 cells but not in HepG2 cells in response to treatment with TCDD. These results provide additional evidence for the induction by TCDD of a novel E2 4-hydroxylase in MCF-7 cells but not in HepG2 cells and indicate possible endocrine regulatory roles for the newly discovered group of enzymes of the CYP1B subfamily.
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PMID:The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on estrogen metabolism in MCF-7 breast cancer cells: evidence for induction of a novel 17 beta-estradiol 4-hydroxylase. 782 86

The expression of CYP1B1 in human mammary fibroblasts (HMFs) was characterized as a potential modulator of their individual function as well as effects on adjacent mammary epithelia. We have used these characteristics to explore the diversity of fibroblast cells isolated from reduction mammoplasty patients and from different breast locations in breast cancer patients (tumors, peripheral to tumor and skin). These parameters have also been used to examine differences between two donors. The results have shown that while none of these HMFs expressed a detectable CYP1A1 protein basally or in response to TCDD, they all expressed CYP1B1 constitutively at similar levels (0.5-0.9 pmol/mg microsomal proteins) and they were induced by TCDD (up to 5-fold) consistent with mediation by the Ah receptor (AhR). DMBA metabolism by HMFs exhibited high proportions of 5,6-, 10,11- and 3,4-dihydrodiols, a profile that is typical of human CYP1B1 regioselectivity. RT-PCR followed by Southern blot analyses demonstrated that CYP1B1 mRNA expression in HMFs parallels levels of respective microsomal proteins. The AhR is expressed in these HMFs as two cytosolic forms (approximately 106 and 104 kDa) and a substantial proportion of the 104 kDa form was localized to the nucleus even prior to TCDD treatment. In all HMFs isolated directly from collagenase digested breast tissues the AhR is expressed at levels 10-fold lower than in breast epithelial cells. However, HMFs that were isolated after serial passaging of mammary epithelial cultures had shown much higher levels of the AhR expression and more dramatic TCDD-induced down-regulation (>80% in 24 h) associated with more efficient nuclear translocation. These differences suggested the presence of two functionally distinct subtypes of HMFs: interstitial stromal fibroblasts that are readily released by collagenase digestion of breast tissues, and lobular stromal fibroblasts which are more tightly associated with the breast epithelia.
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PMID:Expression of CYP1B1 but not CYP1A1 by primary cultured human mammary stromal fibroblasts constitutively and in response to dioxin exposure: role of the Ah receptor. 974 40

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic-metabolizing enzymes, including the cytochrome P450 isozyme, CYP1A1. TCDD-induced 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17beta-estradiol for up to 72 h, with a half-maximal effective concentration (EC50) of 0.9 nM. Reduced enzyme activity was correlated with decreased CYP1A1 mRNA levels, and transcription. Exposure to TCDD plus 17beta-estradiol also reduced CYP1A1 activity in MCF-7 breast cancer cells but not in Hep-3B human liver cells or HuE primary human keratinocytes, suggesting that the effect was specific to estrogen-regulated cells. Estrogen receptor antagonists 4-hydroxytamoxifen and 7alpha-[9-(4,4, 5,5,5-pentafluoro-pentylsulfinyl)nonyl]estra-1,3,5(10)-tr iene3, 17beta-diol restored TCDD-induced CYP1A1 transcription, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mobility shift assay showed that 17beta-estradiol had little effect on Ah receptor binding to its DNA-responsive element. 17beta-Estradiol did not alter the induction of another Ah receptor-regulated gene, CYP1B1, suggesting that altered Ah receptor binding to DNA does not mediate reduced CYP1A1 transcription. Transfecting ECC-1 cells with a general transcription factor involved in CYP1A1 induction, nuclear factor-1, reversed 17beta-estradiol antagonism of dioxin induced-CYP1A1. The data suggest that 17beta-estradiol reduced CYP1A1 expression at the transcriptional level by squelching available nuclear factor-1, a transcription factor that interacts with both Ah and estrogen receptors.
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PMID:Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells. 992 Aug 87

Cytochrome P450 CYP1B1 is a recently identified member of the CYP1 P450 family. We have shown that this P450 displays increased expression in several types of human cancer, indicating that CYP1B1 is a potential tumor biomarker. In this study we developed monoclonal antibodies (MAbs) to CYP1B1 that are effective on formalin-fixed, paraffin-embedded tissue sections and investigated the presence of CYP1B1 in a series of primary breast cancers. The MAbs were generated using a synthetic peptide coupled to carrier protein as the immunogen. The MAbs specifically recognized CYP1B1 and did not recognize either CYP1A1 or CYP1A2, related CYP1 forms. The MAbs were tested by immunohistochemistry and were found to be effective on formalin-fixed, paraffin-embedded tissue sections. The majority of breast cancers showed positive immunoreactivity for CYP1B1, and in each case CYP1B1 was specifically localized to tumor cells. The presence of CYP1B1 in breast cancer cells is likely to contribute to their metabolism of estradiol because CYP1B1 is a specific estradiol hydroxylase. (J Histochem Cytochem 47:1457-1464, 1999)
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PMID:Immunohistochemical localization of cytochrome P450 CYP1B1 in breast cancer with monoclonal antibodies specific for CYP1B1. 1054 18

The age-specific incidence rate of breast cancer in women rises until menopause, levels off and then rises again at a much lower rate indicating a possible hormonal influence on the disease risk. A large amount of evidence has implicated hormones and other compounds with oestrogen activity in the pathogenesis of certain endocrine cancers, particularly breast cancer. Widely dispersed hormone-like chemicals, capable of disrupting the endocrine system and interfering with proliferation, have been described. Compounds such as dioxins, some polychlorinated biphenyls and the plastic ingredient bisphenol-A have been shown to interfere with human reproduction and hormonal regulation. The levels of these foreign compounds as well as the levels of endogenous oestradiol may influence the risk of breast cancer. Endogenous oestradiol is synthesised in the ovarian theca cells of premenopausal women or in the stromal adipose cells of the breast of postmenopausal women and minor quantities in peripheral tissue. These cells, as well as breast cancer tissue, express all the necessary enzymes for this synthesis: CYP17, CYP11a, CYP19, hydroxysteroid hydrogenase, steroid sulphatase as well as enzymes further hydroxylating oestradiol such as CYP1A1, CYP3A4, CYP1B1. Polymorphisms in these enzymes may have a possible role in the link between environmental estrogens and hormone-like substances and the interindividual risk of breast cancer.
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PMID:Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. 1076 42

Estrogen exposure represents the major known risk factor for development of breast cancer in women and is implicated in the development of prostate cancer in men. Human breast tissue has been shown to be a site of oxidative metabolism of estrogen due to the presence of specific cytochrome P450 enzymes. The oxidative metabolism of 17beta-estradiol (E2) to E2-3,4-quinone metabolites by an E2-4-hydroxylase in breast tissue provides a rational hypothesis to explain the mammary carcinogenic effects of estrogen in women because this metabolite is directly genotoxic and can undergo redox cycling to form genotoxic reactive oxygen species. In this chapter, evidence in support of this hypothesis and of the role of P4501B1 as the 4-hydroxylase expressed in human breast tissue is reviewed. However, the plausibility of this hypothesis has been questioned on the grounds that insufficient E2 is present in breast tissue to be converted to biologically significant amounts of metabolite. This critique is based on the assumption that plasma and tissue E2 levels are concordant. However, breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than predicted from plasma levels. Consequently, factors must be present to alter breast tissue E2 levels independently of plasma concentrations. One such factor may be the local production of E2 in breast tissue through the enzyme aromatase, and the evidence supporting the expression of aromatase in breast tissue is also reviewed in this chapter. If correct, mutations or environmental factors enhancing aromatase activity might result in high tissue concentrations of E2 that would likely be sufficient to serve as substrates for CYP1B1, given its high affinity for E2. This concept, if verified experimentally, would provide plausibility to the hypothesis that sufficient E2 may be present in tissue for formation of catechol metabolites that are estrogenic and which, upon further oxidative metabolism, form genotoxic species at levels that may contribute to estrogen carcinogenesis.
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PMID:Tissue-specific synthesis and oxidative metabolism of estrogens. 1096 22

2-(4-Amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) is a candidate antitumor agent with potent and selective activity against human-derived tumor cell lines in vitro and in vivo. Only sensitive cell lines (e.g., MCF-7) were able to accumulate and metabolize DF 203, forming the main inactive metabolite, 2-(4-amino-3-methylphenyl)-6-hydroxybenzothiazole (6-OH 203). Selective metabolism may therefore underlie its antitumor profile. DF 203 6-hydroxylase activity by MCF-7 cells was not constitutive but induced only after pretreatment of cells with DF 203, 3-methylcholanthrene, or beta-naphthoflavone. 6-Hydroxylation was strongly inhibited by either goat antirat cytochrome P450 1A1 (CYP1A1) serum or alpha-naphthoflavone. Both alpha-naphthoflavone and 6-OH 203 abrogated DF 203-induced growth inhibition. Microsomes from genetically engineered human B-lymphoblastoid cells expressing CYP1A1, CYP1B1, or CYP2D6 metabolized DF 203 to 6-OH 203. Immunoblot analysis detected significantly enhanced CYP1A1 protein in a panel of sensitive breast cancer cell lines after exposure to DF 203. Neither constitutive expression nor induction of CYP1A1 protein was detected in nonresponsive breast (HBL 100, MDA-MB-435, and MCF-7/ADR) and prostate (PC 3 and DU 145) cancer cell lines. The expression of CYP1B1 was also modulated by DF 203 in the same sensitive cell lines. However, of the two isoforms, only CYP1A1 activity was irreversibly inhibited by DF 203 and significantly inhibited by 6-OH 203. In sensitive cell lines only, [14C]DF 203-derived radioactivity bound covalently to a Mr 50,000, protein which was immunoprecipitated by CYP1A1 antiserum. The covalent binding of [14C]DF 203 to recombinant CYP1A1 enzyme was NADPH-dependent and reduced by 6-OH 203 and glutathione. CYP1A1 appears essential for the metabolism of DF 203 and may have a pivotal, yet undefined, role in its antitumor activity.
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PMID:Role of Cyp1A1 in modulation of antitumor properties of the novel agent 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells. 1101 48

The expression of CYP1A1 and CYP1B1, encoding enzymes known to play a central role in oxidative metabolism of a wide range of compounds including steroids, was significantly increased in anti-estrogen-resistant human breast cancer cell lines. This was a purely regulatory phenomenon because no gene amplification had occurred. In anti-estrogen-sensitive MCF-7 cells, the steroidal anti-estrogen, ICI 182780, is able to induce the expression of the arylhydrocarbon receptor (AhR)-regulated gene product, CYP1A1, via an estrogen receptor (ER)- mediated process. This observation suggests cross-talk between the AhR and ER systems. Surprisingly, the increased constitutive expression in anti-estrogen-resistant cells of CYP1A1 and CYP1B1 mRNAs, encoding detoxification enzymes, had no effect on the activity of the ICI 182780 compound. The ICI 182780 regulation of estradiol-inducible genes was found to be identical in the resistant and sensitive breast cancer cell lines. In conclusion, anti-estrogen resistance is not due to conversion of ICI 182780 to less active compounds.
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PMID:Increased expression of cytochrome p450 1A1 and 1B1 genes in anti-estrogen-resistant human breast cancer cell lines. 1109 12

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