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Published in: Breast Cancer Research and Treatment 3/2008

01-08-2008 | Epidemiology

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

Authors: Vanesa Martinez, Susan Kennedy, Padraig Doolan, Patrick Gammell, Helena Joyce, Elaine Kenny, Jai Prakash Mehta, Eoin Ryan, Robert O’Connor, John Crown, Martin Clynes, Lorraine O’Driscoll

Published in: Breast Cancer Research and Treatment | Issue 3/2008

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Abstract

The complex role of drug metabolism-related enzymes and their possible influence in cancer development, treatment and outcome has not yet been completely elucidated. There is evidence that these enzymes can activate certain environmental procarcinogens to more toxic derivatives and thus a role has been proposed for them in carcinogenesis. The fact that they can also inactivate a number of chemotherapeutic drugs has raised the possibility of these enzymes influencing the sensitivity of tumour cells to anticancer agents. In this report, we analyse the expression of drug metabolism-related genes within a whole genome microarray study of 104 breast cancer and 17 normal breast specimens. Kaplan–Meier survival curves, Chi-squared, and Cox Regression analyses were used to identify associations between expression of gene transcripts and patients’ clinicopathological and survival data. Our results show that several of these genes are significantly expressed in both normal and tumour tissue; in many cases, expression is altered in the tumour specimens as compared to normal breast tissue. Moreover, expression of ARNT2 and GST A1 was correlated with prognosis. Kaplan–Meier analysis showed expression of ARNT2 mRNA to correlate significantly with favourable disease outcome for patients, in terms of both their disease-free survival (P = 0.0094) and overall survival (P = 0.0018) times from diagnosis, while detection of GST A1 mRNA correlated with shortened disease-free survival (P = 0.0131) and overall survival (P = 0.0028). Multivariate analysis indicated GST A1 expression to be an independent prognostic factor for overall survival (P = 0.045). Our results suggest a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers.
Literature
1.
go back to reference Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D (2000) The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues. Cancer Lett 1:7–16CrossRef Perquin M, Oster T, Maul A, Froment N, Untereiner M, Bagrel D (2000) The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues. Cancer Lett 1:7–16CrossRef
2.
go back to reference Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 6:343–352CrossRef Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 6:343–352CrossRef
3.
go back to reference Oyama T, Kagawa N, Kunugita N, Kitagawa K, Ogawa M, Yamaguchi T, Suzuki R, Kinaga T, Yashima Y, Ozaki S et al (2004) Expression of cytochrome P450 in tumor tissues and its association with cancer development. Front Biosci 1967–1976 Oyama T, Kagawa N, Kunugita N, Kitagawa K, Ogawa M, Yamaguchi T, Suzuki R, Kinaga T, Yashima Y, Ozaki S et al (2004) Expression of cytochrome P450 in tumor tissues and its association with cancer development. Front Biosci 1967–1976
4.
go back to reference Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 12:947–960CrossRef Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 12:947–960CrossRef
5.
go back to reference Rodriguez-Antona C, Ingelman-Sundberg M (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene 11:1679–1691CrossRef Rodriguez-Antona C, Ingelman-Sundberg M (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene 11:1679–1691CrossRef
6.
go back to reference Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW et al (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1:1–42CrossRef Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW et al (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1:1–42CrossRef
7.
go back to reference Yu LJ, Matias J, Scudiero DA, Hite KM, Monks A, Sausville EA, Waxman DJ (2001) P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab Dispos 3:304–312 Yu LJ, Matias J, Scudiero DA, Hite KM, Monks A, Sausville EA, Waxman DJ (2001) P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab Dispos 3:304–312
8.
go back to reference Dhaini HR, Thomas DG, Giordano TJ, Johnson TD, Biermann JS, Leu K, Hollenberg PF, Baker LH (2003) Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol 13:2481–2485CrossRef Dhaini HR, Thomas DG, Giordano TJ, Johnson TD, Biermann JS, Leu K, Hollenberg PF, Baker LH (2003) Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol 13:2481–2485CrossRef
9.
go back to reference Nebert DW, Vasiliou V (2004) Analysis of the glutathione S-transferase (GST) gene family. Hum Genomics 6:460–464 Nebert DW, Vasiliou V (2004) Analysis of the glutathione S-transferase (GST) gene family. Hum Genomics 6:460–464
10.
go back to reference Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 11:4707–4715CrossRef Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Xiao X, Zeldin DC, Wang DW (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 11:4707–4715CrossRef
11.
go back to reference Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR et al (1999) Regulation of JNK signaling by GSTp. EMBO J 5:1321–1334CrossRef Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR et al (1999) Regulation of JNK signaling by GSTp. EMBO J 5:1321–1334CrossRef
12.
go back to reference Tew KD, Ronai Z (1999) GST function in drug and stress response. Drug Resist Updat 3:143–147CrossRef Tew KD, Ronai Z (1999) GST function in drug and stress response. Drug Resist Updat 3:143–147CrossRef
13.
go back to reference Murray GI, Taylor MC, McFadyen MC, McKay JA, Greenlee WF, Burke MD, Melvin WT (1997) Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res 14:3026–3031 Murray GI, Taylor MC, McFadyen MC, McKay JA, Greenlee WF, Burke MD, Melvin WT (1997) Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res 14:3026–3031
14.
go back to reference Iscan M, Klaavuniemi T, Coban T, Kapucuoglu N, Pelkonen O, Raunio H (2001) The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat 1:47–54CrossRef Iscan M, Klaavuniemi T, Coban T, Kapucuoglu N, Pelkonen O, Raunio H (2001) The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue. Breast Cancer Res Treat 1:47–54CrossRef
15.
go back to reference Muskhelishvili L, Thompson PA, Kusewitt DF, Wang C, Kadlubar FF (2001) In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J Histochem Cytochem 229–236 Muskhelishvili L, Thompson PA, Kusewitt DF, Wang C, Kadlubar FF (2001) In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J Histochem Cytochem 229–236
16.
go back to reference Kapucuoglu N, Coban T, Raunio H, Pelkonen O, Edwards RJ, Boobis AR, Iscan M (2003) Expression of CYP3A4 in human breast tumour and non-tumour tissues. Cancer Lett 1:17–23CrossRef Kapucuoglu N, Coban T, Raunio H, Pelkonen O, Edwards RJ, Boobis AR, Iscan M (2003) Expression of CYP3A4 in human breast tumour and non-tumour tissues. Cancer Lett 1:17–23CrossRef
17.
go back to reference Page DL, Andersen AT (1987) Diagnostic histopathology. Churchill Livingstone, London, Melbourne and New York Page DL, Andersen AT (1987) Diagnostic histopathology. Churchill Livingstone, London, Melbourne and New York
18.
go back to reference Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathol 403–410 Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathol 403–410
19.
go back to reference Sobin LH, Wittekind C (1997). TNM classification of malignant tumours. John Wiley and Sons, New York Sobin LH, Wittekind C (1997). TNM classification of malignant tumours. John Wiley and Sons, New York
20.
go back to reference O’Driscoll L, McMorrow J, Doolan P, McKiernan E, Mehta JP, Ryan E, Gammell P, Joyce H, O’Donovan N, Walsh N et al (2006) Investigation of the molecular profile of basal cell carcinoma using whole genome microarrays. Mol Cancer 74 O’Driscoll L, McMorrow J, Doolan P, McKiernan E, Mehta JP, Ryan E, Gammell P, Joyce H, O’Donovan N, Walsh N et al (2006) Investigation of the molecular profile of basal cell carcinoma using whole genome microarrays. Mol Cancer 74
21.
go back to reference Karlgren M, Gomez A, Stark K, Svard J, Rodriguez-Antona C, Oliw E, Bernal ML, Ramon y Cajal S, Johansson I, Ingelman-Sundberg M (2006) Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1. Biochem Biophys Res Commun 2:451–458CrossRef Karlgren M, Gomez A, Stark K, Svard J, Rodriguez-Antona C, Oliw E, Bernal ML, Ramon y Cajal S, Johansson I, Ingelman-Sundberg M (2006) Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1. Biochem Biophys Res Commun 2:451–458CrossRef
22.
go back to reference El-Rayes BF, Ali S, Heilbrun LK, Lababidi S, Bouwman D, Visscher D, Philip PA (2003) Cytochrome p450 and glutathione transferase expression in human breast cancer. Clin Cancer Res 5:1705–1709 El-Rayes BF, Ali S, Heilbrun LK, Lababidi S, Bouwman D, Visscher D, Philip PA (2003) Cytochrome p450 and glutathione transferase expression in human breast cancer. Clin Cancer Res 5:1705–1709
23.
go back to reference Liloglou T, Walters M, Maloney P, Youngson J, Field JK (2002) A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer. Lung Cancer 2:143–146CrossRef Liloglou T, Walters M, Maloney P, Youngson J, Field JK (2002) A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer. Lung Cancer 2:143–146CrossRef
24.
go back to reference Brigelius-Flohe R, Muller C, Menard J, Florian S, Schmehl K, Wingler K (2001) Functions of GI-GPx: lessons from selenium-dependent expression and intracellular localization. Biofactors 1–4:101–106 Brigelius-Flohe R, Muller C, Menard J, Florian S, Schmehl K, Wingler K (2001) Functions of GI-GPx: lessons from selenium-dependent expression and intracellular localization. Biofactors 1–4:101–106
25.
go back to reference Chu FF, Esworthy RS, Lee L, Wilczynski S (1999) Retinoic acid induces Gpx2 gene expression in MCF-7 human breast cancer cells. J Nutr 10:1846–1854 Chu FF, Esworthy RS, Lee L, Wilczynski S (1999) Retinoic acid induces Gpx2 gene expression in MCF-7 human breast cancer cells. J Nutr 10:1846–1854
26.
go back to reference Woenckhaus M, Klein-Hitpass L, Grepmeier U, Merk J, Pfeifer M, Wild P, Bettstetter M, Wuensch P, Blaszyk H, Hartmann A et al (2006) Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. J Pathol 2:192–204CrossRef Woenckhaus M, Klein-Hitpass L, Grepmeier U, Merk J, Pfeifer M, Wild P, Bettstetter M, Wuensch P, Blaszyk H, Hartmann A et al (2006) Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. J Pathol 2:192–204CrossRef
27.
go back to reference van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 6871:530–536CrossRef van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 6871:530–536CrossRef
28.
go back to reference Maltepe E, Keith B, Arsham AM, Brorson JR, Simon MC (2000) The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Biochem Biophys Res Commun 1:231–238CrossRef Maltepe E, Keith B, Arsham AM, Brorson JR, Simon MC (2000) The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Biochem Biophys Res Commun 1:231–238CrossRef
29.
go back to reference Freeburg PB, Abrahamson DR (2004) Divergent expression patterns for hypoxia-inducible factor-1beta and aryl hydrocarbon receptor nuclear transporter-2 in developing kidney. J Am Soc Nephrol 10:2569–2578CrossRef Freeburg PB, Abrahamson DR (2004) Divergent expression patterns for hypoxia-inducible factor-1beta and aryl hydrocarbon receptor nuclear transporter-2 in developing kidney. J Am Soc Nephrol 10:2569–2578CrossRef
30.
go back to reference Hosoya T, Oda Y, Takahashi S, Morita M, Kawauchi S, Ema M, Yamamoto M, Fujii-Kuriyama Y (2001) Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice. Genes Cells 4:361–374CrossRef Hosoya T, Oda Y, Takahashi S, Morita M, Kawauchi S, Ema M, Yamamoto M, Fujii-Kuriyama Y (2001) Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice. Genes Cells 4:361–374CrossRef
31.
go back to reference Hsu HJ, Wang WD, Hu CH (2001) Ectopic expression of negative ARNT2 factor disrupts fish development. Biochem Biophys Res Commun 2:487–492CrossRef Hsu HJ, Wang WD, Hu CH (2001) Ectopic expression of negative ARNT2 factor disrupts fish development. Biochem Biophys Res Commun 2:487–492CrossRef
32.
go back to reference Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH (2006) A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem 9:1175–1187CrossRef Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH (2006) A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem 9:1175–1187CrossRef
33.
go back to reference Tanner B, Hengstler JG, Dietrich B, Henrich M, Steinberg P, Weikel W, Meinert R, Kaina B, Oesch F, Knapstein PG (1997) Glutathione, glutathione S-transferase alpha and pi, and aldehyde dehydrogenase content in relationship to drug resistance in ovarian cancer. Gynecol Oncol 1:54–62CrossRef Tanner B, Hengstler JG, Dietrich B, Henrich M, Steinberg P, Weikel W, Meinert R, Kaina B, Oesch F, Knapstein PG (1997) Glutathione, glutathione S-transferase alpha and pi, and aldehyde dehydrogenase content in relationship to drug resistance in ovarian cancer. Gynecol Oncol 1:54–62CrossRef
34.
go back to reference Peters WH, Roelofs HM, van Putten WL, Jansen JB, Klijn JG, Foekens JA (1993) Response to adjuvant chemotherapy in primary breast cancer: no correlation with expression of glutathione S-transferases. Br J Cancer 1:86–92 Peters WH, Roelofs HM, van Putten WL, Jansen JB, Klijn JG, Foekens JA (1993) Response to adjuvant chemotherapy in primary breast cancer: no correlation with expression of glutathione S-transferases. Br J Cancer 1:86–92
35.
go back to reference Alpert LC, Schecter RL, Berry DA, Melnychuk D, Peters WP, Caruso JA, Townsend AJ, Batist G (1997) Relation of glutathione S-transferase alpha and mu isoforms to response to therapy in human breast cancer. Clin Cancer Res 5:661–667 Alpert LC, Schecter RL, Berry DA, Melnychuk D, Peters WP, Caruso JA, Townsend AJ, Batist G (1997) Relation of glutathione S-transferase alpha and mu isoforms to response to therapy in human breast cancer. Clin Cancer Res 5:661–667
36.
go back to reference Wrigley EC, McGown AT, Buckley H, Hall A, Crowther D (1996) Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome. Br J Cancer 6:763–769 Wrigley EC, McGown AT, Buckley H, Hall A, Crowther D (1996) Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome. Br J Cancer 6:763–769
37.
go back to reference Sweeney C, Ambrosone CB, Joseph L, Stone A, Hutchins LF, Kadlubar FF, Coles BF (2003) Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment. Int J Cancer 6:810–814CrossRef Sweeney C, Ambrosone CB, Joseph L, Stone A, Hutchins LF, Kadlubar FF, Coles BF (2003) Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment. Int J Cancer 6:810–814CrossRef
Metadata
Title
Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue
Authors
Vanesa Martinez
Susan Kennedy
Padraig Doolan
Patrick Gammell
Helena Joyce
Elaine Kenny
Jai Prakash Mehta
Eoin Ryan
Robert O’Connor
John Crown
Martin Clynes
Lorraine O’Driscoll
Publication date
01-08-2008
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2008
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-007-9739-9

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