Abstract
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 CYP1A1 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.
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Davis DL, Bradlow HL, Wolff M, Woodruff T, Hoel DG, Anton V, Culver H: Medical hypothesis: xenoestrogens as preventable causes of breast cancer. Environ Health Perspect 101: 372-377, 1993
Morris JJ, Seifter E: The role of aromatic hydrocarbons in the genesis of breast cancer. Med Hypothesis 38: 177-184, 1992
Nebert DW: Role of genetics and drug metabolism in human cancer risk. Mutat Res 247: 267-281, 1991
Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW: P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6: 1-42, 1996
Spink DC, Eugster HP, Lincoln DW, Schuetz JD, Schuetz EG, Johnson JA, Kaminsky LS, Gierthy JF: 17?-Estradiol hydroxylation catalyzed by cytochrome P4501A1: a comparison of the activities induced by 2, 3, 7, 8-tetrachlorodibenzop-dioxin in MCF-7 cells with those from heterologous expression of the cDNA. Arch Biochem Biophys 293: 342-348, 1992
Suto A, Bradlow HL, Wong GY, Osborn MP, Telang NT: Experimental down regulation of intermediate biomarkers of carcinogenesis in mouse mammary epithelial cells. Breast Cancer Res Treat 27: 193-202, 1993
Falck F, Ricci M, Wolff M, Godbold J, Deckers P: Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to cancer. Arch Environ Health 47: 143-146, 1992
Denison MS, Whitlock JP: Xenobiotic-inducible transcription of cytochrome P450 genes. J Biol Chem 270: 18175-18178, 1995
Nebert DW, Gonzales FJ: P450 genes: structure, evolution and regulation. Ann Rev Biochem 56: 945-993, 1987
Savas U, Bhattacharyya K, Christou M, Alexander D, Jefcoate CR: Mouse cytochrome p450EF: representative of a new 1B subfamily of cytochrome P450s. Cloning, sequence determination and tissue expression. J Biol Chem 269: 14905-14911, 1994
Bhattacharyya K, Brake P, Eltom SE, Otto S, Jefcoate CR: Identification of a rat adrenal cytochrome P450 active in polycyclic hydrocarbon metabolism as rat CYP1B1. Demonstration of a unique tissue-specific pattern of hormonal and aryl hydrocarbon receptor-linked regulation. J Biol Chem 270: 11595-11602, 1995
Shimada T, Hayes CL, Yamazaki H, Amin S, Hecht SS, Guengerich FP, Sutter TR: Activation of chemically diverse procarcinogens by human cytochrome P450 1B1. Cancer Res 56: 2979-2984, 1996
Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR: 17?-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA 93: 9776-9781, 1996
Liehr JG, Ricci MJ: 4-hydroxylation of estrogens as marker of human mammary tumors. Proc Natl Acad Sci USA 93: 3294-3296, 1996
Guengerich FP, Shimada T: Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol 4: 391-407, 1991
Yamazaki H, Inui Y, Yun CH, Guengerich FP, Shimada T: Cytochrome P450 2E1 and 2A6 enzymes as a major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. Carcinogenesis 13: 1789-1794, 1992
Shou M, Korzekwa KR, Crespi CL, Gonzalez FJ, Gelboin HV: The role of 12 cDNA-expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans-7,8-dihydrodiol. Mol Carcinogen 10: 159-168, 1994
Miyamoto S, Guzman RC, Osborne RC, Nandi S: Neoplastic transformation of mouse mammary epithelial cells by in vitro exposure to N-methyl-N-nitrosourea. Proc Natl Acad Sci USA 85: 477-481, 1988
Nouso K, Thorgeirsson SS, Battula N: Stable expression of human cytochrome P450IIE1 in mammalian cells: metabolic activation of nitrosodimethylamine and formation of adducts with cellular DNA. Cancer Res 52: 1796-1800, 1992
Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL: Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst 84: 634-638, 1992
Huang Z, Guengerich FP, Kaminsky LS: 16?-hydroxylation of estrone by human cytochrome P4503A4/5. Carcinogenesis 19: 867-872, 1998
Crewe HK, Ellis SW, Lennard MS, Tucker GT: Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 53: 171-178, 1997
Murray GI, Foster CO, Barnes TS, Weaver RJ, Ewen SWB, Melvin WT, Burke MD: Expression of cytochrome P450IA in breast cancer. Br J Cancer 63: 1021-1023, 1991
Albin N, Massaad L, Toussaint C, Matthieu MC, Morizet J, Parise O, Gouyette A, Chabot GG: Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. Cancer Res 53: 3541-3546, 1993
Huang Z, Fasco MJ, Figge HL, Keyomarsi K, Kaminsky LS: Expression of cytochromes P450 in human breast tissue and tumors. Drug Metab Dispos 24: 899-905, 1996
Murray GI, Taylor MC, McFayden MCE, McKay JA, Greenlee WF, Burke MD, Melvin WT: Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res 57: 3026-3031, 1997
McKay JA, Melvin WT, Ah-See AK, Ewen SWB, Greenlee WF, Marcus CB, Burke MD, Murray GI: Expression of cytochrome P450 1B1 in breast cancer. FEBS Lett 374: 270-272, 1995
McFadyen MC, Breeman S, Payne S, Stirk C, Miller ID, Melvin WT, Murray GI: Immunohistochemical localization of cytochrome P450 CYP1B1 in breast cancer with monoclonal antibodies specific for CYP1B1. J Histochem Cytochem 47: 1457-1464, 1999
Eltom SE, Larsen MC, Jefcoate CR: 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. Carcinogenesis 19: 1437-1444, 1998
Hellmold H, Rylander T, Magnusson M, Reihner E, Warner M, Gustafsson J-A: Characterization of cytochrome P450 enzymes in human breast tissue from reduction mammaplasties. J Clin Endocrinol Metab 43: 886-895, 1998
Larsen MC, Angus WGR, Brake PB, Eltom SE, Sukow KA, Jefcoate CR: Characterization of CYP1B1 and CYP1A1 expression in human mammary epithelial cells: role of the aryl hydrocarbon receptor in polycyclic aromatic hydrocarbon metabolism. Cancer Res 58: 2366-2374, 1998
Spink DC, Spink BC, Cao JQ, DePasquale JA, Pentecost BT, Fasco MJ, Li Y, Sutter TR: Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells. Carcinogenesis 19: 291-298, 1998
Hakkola J, Pasanen M, Hukkanen J, Pelkonen O, Maenpaa J, Edwards RJ, Boobis AR, Raunio H: Expression of xenobiotic-metabolizing cytochrome P450 forms in human full-term placenta. Biochem Pharmacol 51: 403-411, 1996
Hakkola J, Pasanen M, Pelkonen O, Hukkanen J, Evisalmi S, Anttila S, Rane A, Mantyla M, Purkunen R, Saarikoski S, Raunio H: Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells. Carcinogenesis 18: 391-397, 1997
Koskela S, Hakkola J, Hukkanen J, Pelkonen O, Sorri M, Saranen A, Anttila S, Fernandez-Salguero P, Gonzalez F, Raunio H: Expression of CYP2A genes in human liver and extrahepatic tissues. Biochem Pharmacol 57: 1407-1413, 1999
Forrester LM, Hayes JD, Millis R, Barnes D, Harris AL, Schlager JJ, Powis G, Wolf CR: Expression of glutathione Stransferases and cytochrome P450 in normal and tumor breast tissue. Carcinogenesis 11: 2163-2170, 1990
Yokose T, Doy M, Taniguchi T, Shimada T, Kakiki M, Horie T, Matsuzaki Y, Mukai K: Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues. Virchows Arch 434: 401-411, 1999
Murray GI, Weaver RJ, Paterson PJ, Ewen SWB, Melvin WT, Burke MD: Expression of xenobiotic metabolizing enzymes in breast cancer. J Pathol 169: 347-353, 1993
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Iscan, M., Klaavuniemi, T., Çoban, T. et al. The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat 70, 47–54 (2001). https://doi.org/10.1023/A:1012526406741
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DOI: https://doi.org/10.1023/A:1012526406741