Relationship between intratumoral expression of genes coding for xenobiotic-metabolizing enzymes and benefit from adjuvant tamoxifen in estrogen receptor alpha-positive postmenopausal breast carcinoma
Breast Cancer Research - 2004
Tóm tắt
Little is known of the function and clinical significance of intratumoral dysregulation of xenobiotic-metabolizing enzyme expression in breast cancer. One molecular mechanism proposed to explain tamoxifen resistance is altered tamoxifen metabolism and bioavailability. To test this hypothesis, we used real-time quantitative RT-PCR to quantify the mRNA expression of a large panel of genes coding for the major xenobiotic-metabolizing enzymes (12 phase I enzymes, 12 phase II enzymes and three members of the ABC transporter family) in a small series of normal breast (and liver) tissues, and in estrogen receptor alpha (ERα)-negative and ERα-positive breast tumors. Relevant genes were further investigated in a well-defined cohort of 97 ERα-positive postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone. Seven of the 27 genes showed very weak or undetectable expression in both normal and tumoral breast tissues. Among the 20 remaining genes, seven genes (CYP2A6, CYP2B6, FMO5, NAT1, SULT2B1, GSTM3 and ABCC11) showed significantly higher mRNA levels in ERα-positive breast tumors than in normal breast tissue, or showed higher mRNA levels in ERα-positive breast tumors than in ERα-negative breast tumors. In the 97 ERα-positive breast tumor series, most alterations of these seven genes corresponded to upregulations as compared with normal breast tissue, with an incidence ranging from 25% (CYP2A6) to 79% (NAT1). Downregulation was rare. CYP2A6, CYP2B6, FMO5 and NAT1 emerged as new putative ERα-responsive genes in human breast cancer. Relapse-free survival was longer among patients with FMO5-overexpressing tumors or NAT1-overexpressing tumors (P = 0.0066 and P = 0.000052, respectively), but only NAT1 status retained prognostic significance in Cox multivariate regression analysis (P = 0.0013). Taken together, these data point to a role of genes coding for xenobiotic-metabolizing enzymes in breast tumorigenesis, NAT1 being an attractive candidate molecular predictor of antiestrogen responsiveness.
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Tài liệu tham khảo
McGuire WL: Steroid hormone receptors in breast cancer treatment strategy. Recent Prog Horm Res. 1980, 36: 135-156.
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998, 351: 1451-1467. 10.1016/S0140-6736(97)11423-4.
Osborne CK: Mechanisms for tamoxifen resistance in breast cancer: possible role of tamoxifen metabolism. J Steroid Biochem Mol Biol. 1993, 47: 83-89. 10.1016/0960-0760(93)90060-A.
Katzenellenbogen BS, Montano MM, Ekena K, Herman ME, McInerney EM: William L. McGuire Memorial Lecture. Antiestrogens: mechanisms of action and resistance in breast cancer. Breast Cancer Res Treat. 1997, 44: 23-38. 10.1023/A:1005835428423.
Ali S, Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002, 2: 101-112. 10.1038/nrc721.
MacGregor JI, Jordan VC: Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev. 1998, 50: 151-196.
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. 1997, 53: 171-178. 10.1016/S0006-2952(96)00650-8.
Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM: Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002, 30: 869-874. 10.1124/dmd.30.8.869.
Davies AM, Malone ME, White IN: Peroxidase activation of 4-hydroxytamoxifen to cause DNA damage in vitro [abstract]. Biochem Soc Trans. 1995, 23: 439S-
Wiebe VJ, Osborne CK, McGuire WL, DeGregorio MW: Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol. 1992, 10: 990-994.
Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998, 339: 1609-1618. 10.1056/NEJM199811263392207.
Zhang F, Fan PW, Liu X, Shen L, van Breeman RB, Bolton JL: Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4-dihydroxytamoxifen-o-quinone. Chem Res Toxicol. 2000, 13: 53-62. 10.1021/tx990145n.
Fan PW, Bolton JL: Bioactivation of tamoxifen to metabolite E quinone methide: reaction with glutathione and DNA. Drug Metab Dispos. 2001, 29: 891-896.
Dehal SS, Kupfer D: Evidence that the catechol 3,4-dihydroxytamoxifen is a proximate intermediate to the reactive species binding covalently to proteins. Cancer Res. 1996, 56: 1283-1290.
White IN: Tamoxifen: is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans. Curr Drug Metab. 2003, 4: 223-239.
Ramakrishna KV, Fan PW, Boyer CS, Dalvie D, Bolton JL: Oxo substituents markedly alter the phase II metabolism of alpha-hydroxybutenylbenzenes: models probing the bioactivation mechanisms of tamoxifen. Chem Res Toxicol. 1997, 10: 887-894. 10.1021/tx970060r.
Chen G, Yin S, Maiti S, Shao X: 4-Hydroxytamoxifen sulfation metabolism. J Biochem Mol Toxicol. 2002, 16: 279-285. 10.1002/jbt.10048.
Allen PG, Kolesar JM: NAD(P)H: quinone oxidoreductase enhances proliferation inhibition by 4-hydroxytamoxifen. Anti-cancer Res. 2002, 22: 1475-1480.
Williams JA, Phillips DH: Mammary expression of xenobiotic metabolizing enzymes and their potential role in breast cancer. Cancer Res. 2000, 60: 4667-4677.
Osborne CK, Wiebe VJ, McGuire WL, Ciocca DR, DeGregorio MW: Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol. 1992, 10: 304-310.
Brockdorff BL, Skouv J, Reiter BE, Lykkesfeldt AE: Increased expression of cytochrome p450 1A1 and 1B1 genes in anti-estrogen-resistant human breast cancer cell lines. Int J Cancer. 2000, 88: 902-906. 10.1002/1097-0215(20001215)88:6<902::AID-IJC10>3.0.CO;2-C.
Fritz P, Murdter TE, Eichelbaum M, Siegle I, Weissert M, Zanger UM: Microsomal epoxide hydrolase expression as a predictor of tamoxifen response in primary breast cancer: a retrospective exploratory study with long-term follow-up. J Clin Oncol. 2001, 19: 3-9.
Bieche I, Parfait B, Laurendeau I, Girault I, Vidaud M, Lidereau R: Quantification of estrogen receptor alpha and beta expression in sporadic breast cancer. Oncogene. 2001, 20: 8109-8115. 10.1038/sj.onc.1204917.
Hanley JA, McNeil BJ: The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982, 143: 29-36.
Kaplan EL, Meier P: Nonparametric estimation of incomplete observations. J Am Stat Assoc. 1958, 53: 457-481.
Cox DR: Regression models and life tables. J R Stat Soc (B). 1972, 34: 187-220.
Larsen MC, Angus WG, 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. 1998, 58: 2366-2374.
Goth-Goldstein R, Stampfer MR, Erdmann CA, Russell M: Interindividual variation in CYP1A1 expression in breast tissue and the role of genetic polymorphism. Carcinogenesis. 2000, 21: 2119-2122. 10.1093/carcin/21.11.2119.
Huang Z, Fasco MJ, Figge HL, Keyomarsi K, Kaminsky LS: Expression of cytochromes P450 in human breast tissue and tumors. Drug Metab Dispos. 1996, 24: 899-905.
Iscan M, Klaavuniemi T, Coban T, Kapucuoglu N, Pelkonen O, Raunio H: The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat. 2001, 70: 47-54. 10.1023/A:1012526406741.
Ambrosone CB, Sweeney C, Coles BF, Thompson PA, McClure GY, Korourian S, Fares MY, Stone A, Kadlubar FF, Hutchins LF: Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res. 2001, 61: 7130-7135.
Sweeney C, McClure GY, Fares MY, Stone A, Coles BF, Thompson PA, Korourian S, Hutchins LF, Kadlubar FF, Ambrosone CB: Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res. 2000, 60: 5621-5624.
Maugard CM, Charrier J, Pitard A, Campion L, Akande O, Pleasants L, Ali-Osman F: Genetic polymorphism at the glutathione S-transferase (GST) P1 locus is a breast cancer risk modifier. Int J Cancer. 2001, 91: 334-339. 10.1002/1097-0215(200002)9999:9999<::AID-IJC1057>3.0.CO;2-H.
Zheng W, Deitz AC, Campbell DR, Wen WQ, Cerhan JR, Sellers TA, Folsom AR, Hein DW: N-acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1999, 8: 233-239.
Pompeo F, Brooke E, Kawamura A, Mushtaq A, Sim E: The pharmacogenetics of NAT: structural aspects. Pharmacogenomics. 2002, 3: 19-30.
Sim E, Payton M, Noble M, Minchin R: An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes. Hum Mol Genet. 2000, 9: 2435-2441. 10.1093/hmg/9.16.2435.
Williams JA, Stone EM, Fakis G, Johnson N, Cordell JA, Meinl W, Glatt H, Sim E, Phillips DH: N-acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. Pharmacogenetics. 2001, 11: 373-388. 10.1097/00008571-200107000-00002.
Geylan YS, Dizbay S, Guray T: Arylamine N-acetyltransferase activities in human breast cancer tissues. Neoplasma. 2001, 48: 108-111.