Relationship of Polymorphisms of Glutathione S-Transferase GSTT1 and GSTM1 With the Response to Chemotherapy In Mexican Women with Advanced Breast Cancer


Introduction: Breast cancer is a common disease diagnosed in Mexican women and the first leading cause of death [1]. Heterogeneity in patients’ response to treatment is consistently observed across populations. Glutathione S-transferases (GSTs) are involved in the metabolism of environmental carcinogens, reactive oxygen species and chemotherapeutic agents by catalyzing the glutathione with electrophilic compounds. The deletion of GSTT1 and GSTM1 genes result in loss of enzyme activity. A few studies evaluated the response to treatment and the polymorphisms of GSTT1 and GSTM1. The aim of this work is to make the association of the null polymorphisms of GSTT1 and GSTM1 with the response to chemotherapy basically doxorubicin and cyclophosphamide. Methods: The genotyping of thirty patients with breast cancer was made with the Polymerase chain reaction, to identify the polymorphisms of GSTT1 and GSTM1. We determine the status of Her-2 neu, estrogen and progesterone receptors, then the response to treatment was made with an ultrasound and pathological data. We made the association with the χi2 statistics using a p≤0.05. Results: Using the Sigma Stat 3.5 program and the chi-squared analysis, we do not observe a significant association with the GSTT1+/GSTM1+, GSTT1-/GSTM1+ and GSTT1-/GSTM1-polymorphisms and the better or worse response to cyclophosphamide and doxorubicin. With the Her-2 neu, estrogen and progesterone receptors status, we neither found an association with the response to the therapy. Conclusion: This study suggests that GSTT1 and GSTM1 polymorphisms have no statistical significance between the genotype of women with advanced breast cancer and the response to neoadjuvant chemotherapy, but we can see a clear tendency toward better response with the null genotype.

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O. Soto-Quintana, P. Cabrera-Galeana, G. Téllez-Trevilla, J. Barrera-Franco, A. Juárez-Ramiro and J. Castillo-Cadena, "Relationship of Polymorphisms of Glutathione S-Transferase GSTT1 and GSTM1 With the Response to Chemotherapy In Mexican Women with Advanced Breast Cancer," Journal of Cancer Therapy, Vol. 2 No. 3, 2011, pp. 354-361. doi: 10.4236/jct.2011.23048.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] SINAIS, “Sistema Nacional de Información en Salud. Gobierno Federal, Noviembre 2008,” 2010.
[2] N. Garcia, F. Salamanca, H. Astudillo de la Vega, E. Curiel-QueSada, I. Alvarado, R. Penaloza and D. Arenas, “A Molecular Analysis by Gene Expression Profiling Reveals Bik/NBK over expression in Sporadic Breast Tumor Samples of Mexican Females,” BMC Cancer, Vol. 5, 2005, pp. 93-104. doi:10.1186/1471-2407-5-93
[3] L. Jorde, J. Carey and M. Bamshad, “Genética Médica,” 2nd Edition, Harcourt, Madrid, 2000.
[4] M. E. Brandan and Y. Villasenor, “Detección del Cáncer de Mama: Estado de la Mamografía en México,” Cancerologia, Vol. 1, No. 6, 2006, pp. 147-162.
[5] S. A. Rodríguez Cuevas, F. Guisa-Hohenstein, S. Labastida-Almendaro, R. Espejo-Fonseca, et al., “Resultados del Primer Programa de Detección Oportuna de Cáncer de Mama en México Mediante Pesquisa Conmastografía,” Gaceta Mexicana de Oncología, Vol. 8, No. 3, 2009, pp. 83-95.
[6] Z. Ye and H. Song, “Glutathione s-Transferase Polymorphisms (GSTM1, GSTP1 and GSTT1 and the Risk of Acute Leukaemia: A Systematic Review and Meta Analysis,” European Journal of Cancer, Vol. 41, No. 7, 2005, pp. 980-989. doi:10.1016/j.ejca.2005.01.014
[7] M. Gago-Domínguez, X. Jiang and J. E. Castelao, “Lipid Peroxidation, Oxidative Stress Genes and Dietary Factors in Breast Cancer Protection: A Hypothesis,” Breast Cancer Research, Vol. 9, No. 1, p. 201.
[8] C. Kiyohara, “Genetic Polymorphism of Enzymes Involved in Xenobiotic Metabolism and the Risk of Colorectal Cancer,” Journal of Epidemiology, Vol. 10. No. 5, 2000, pp. 349-360.
[9] D. Sheehan, G. Meade, V. Foley and C. A. Dowd, “Structure, Function and Evolution of Glutathione Transferases: Implications for Classification of Non-mammalian Members of an Ancient Enzyme Superfamily,” Biochemical Journal, Vol. 360, 2001, pp. 1-16. doi:10.1042/0264-6021:3600001
[10] J. M. Allan, C. P. Wild, S. Rollinson, E. V. Willett, A. V. Moorman, G. J. Dovey, P. L. Roddam, E. Roman, R. A. Carthwright and G. J. Morgan, “Polymorphisms in Glutathione S-Transferase P1 is Associated with Susceptibility to Chemotherapy Induced Leukemia,” Proceeding of the National Academy of Sciences of the United States of America, Vol. 98, No. 20, 2001, pp. 11592-11597.
[11] V. R. Arruda, C. S. Lima, C. R. Grignoli, M. B. de Melo, I. Lorand-Metze, F. L. Alberto, S. T. Saad and F. F. Costa, “Increased RISK for Acute Myeloid Leukaemia in Individuals with Glutathione S-Transferase mu1 (GSTM1) and Teta 1 (GSTT1) Gene Defects,” European Journal of Haematology, Vol. 66, No. 6, 2001, pp. 383-388. doi:10.1034/j.1600-0609.2001.066006383.x
[12] A. Rossini, D. C. Rapozo, L. M. Amorim, J. M. Macedo, R. Medina, J. F. Neto, C. V. Gallo and L. F. Pinto, “Frequencies of GSTM1, GSTT1, and GSTP1 Polymorphisms in Brazilian Population,” Genetics and Molecular Research, Vol. 1, No. 3, 2002, pp. 233-240.
[13] D. M. Townsend and K. D. Tew, “The Role of Glutathione-S-Transferase in Anticancer Drug Resistance,” Oncogene, Vol. 22, 2003, pp. 7369-7377.
[14] M. Aydin-Sayitoglu, O. Hatirnaz, N. Erensoy and U. Ozbek, “Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 Genes in the Susceptibility to Acute Leukemias,” American Journal of Hematology, Vol. 81, 2006, pp. 162-170.
[15] G. I. Mossallam, T. M. Abdel Hamid and M. A. Samra, “Gluthation S-transferase GSTM1 and GSTT1 Polymorphisms in Adult Acute Myeloid Leukemia, Its Impact on Toxicity and Response to Chemotherapy,” Journal of Egypt National Cancer Institution, Vol. 18, No. 3, 2006, pp. 264-273.
[16] M. Reis, “Farmacogenética Aplicada al Cáncer: Quimioterapia Individualizada y Especificidad Molecular en Medicina,” Revista Médica de Chile, Vol. 39, No. 4, 2006, pp. 577-586.
[17] A. Khedhaier, E. Hassen, N. Bouaouina, S. Gabbou, J. S. B. Ahmed and L. Chouchane, “Implication of Xenobiotics Metabolizing Enzime Gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) Polymorphisms in Breast Cancer,” BMC Cancer, Vol. 8, 2008, p. 109.
[18] F. Skjelbred, M. S?b?, A. Hjart?ker, T. Grotmol, I. L. Hansteen, K. M. Tveit, G. Hoff and E. H. Kure, “Meat, Vegetables and Genetic Polymorphisms and the Risk of Colorectal Carcinomas and Adenomas,” BMC Cancer, Vol. 7. 2007, p. 228.
[19] P. Bolufer, M. Collado, E. Barragan, M. J. Calasanz, D. Colomer, M. Tormo, M. Gonzalez, S. Brunet, M. Batlle, J. Cervera and M. A. Sanz, “Profile of Polymorphisms of Drug-Metabolising Enzymes and the Risk of Therapy- Related Leukemia,” British Journal of Haematology, Vol. 136, No. 4, 2006, pp. 590-596. doi:10.1111/j.1365-2141.2006.06469.x
[20] E. Goekkurt, S. Hoehn, C. Wolschke, C. Wittmer, C. Stueber, D. K. Hossfeld and J. Stoehlmacher, “Polymorphisms of Glutathione S-Transferases (GST) and Thymydilate Synthase (TS) Novel Predictors for Response and Survival in Gastric Cancer Patients,” British Journal of Cancer, Vol. 94, No. 2, 2006, pp. 281-286. doi:10.1038/sj.bjc.6602891
[21] P. Depeille, P. Cuq, I. Passagne, A. Evrard and L. Vian, “Combined Effects of GSTP1 and MRP1 in Melanoma Drug Resistance,” British Journal of Cancer, Vol. 93, 2005, pp. 216-223. doi:10.1038/sj.bjc.6602681
[22] L. M. Dong, J. D. Potter, E. White, C. M. Ulrich, L. R. Cardon and U. Peters, “Genetic Susceptibility to Cancer. Role of Polymorphisms in Candidate Genes,” The Journal of American Medical Association, Vol. 299, No. 20, 2008, pp. 2423-2436.
[23] T. Pongtheerat, M. Treetrisool and W. Purisa, “Glutathion S-Transferase Polymorphisms in Breast Cancers of Thai Patients,” Asian Pacific Journal of Cancer Review, Vol. 10. No. 1, 2009, pp. 127-132.
[24] M. H. Woo, J. J. Shuster, C. Chen, R. O. Bash, F. G. Behm, B. Camitta, C. A. Felix, B. A. Kamen, C. H. Pui, S. C. Raimondi, N. J. Winick, M. D. Amylon and M. V. Relling, “Glutathione S-Transferase Genotypes in Children Who Develop Treatment Related Acute Myeloid Malignancies,” Leukemia, Vol. 14, No. 2, 2000, pp. 232- 237. doi:10.1038/sj.leu.2401660
[25] A. Buchard, J. J. Sánchez, K. Dalhoff and N. Morling, “Multiplex PCR Detection of GSTM1, GSTT1 and GSTP1 Gene Variants,” The Journal of Molecular Diagnostics, Vol. 9, No. 5, 2007, pp. 612-617. doi:10.2353/jmoldx.2007.070030
[26] A. Khedhaier, S. Remadi, M. Corbex, S. B. Ahmed, N. Bouaouina, S. Mestiri, R. Azaiez, A. N. Helal and L. Chouchane, “Glutathione S-Transferases (GSTT1 and GSTM1) Gene Deletions in Tunisians: Susceptibility and Prognostic Implications in Breast Carcinoma,” British Journal of Cancer, Vol. 89, 2003, pp. 1502-1507. doi:10.1038/sj.bjc.6601292
[27] S. M. Davies, L. L. Robison, J. D. Bucley, T. Tjoa, W. G. Woods, G. A. Radloff, J. A. Ross and J. P. Parenthesis, “Glutation S-Transferase Polymorphisms and Outcome of Chemotherapy in Childhood Acute Myeloid Leukemia,” Journal of Clinic Oncology, Vol. 19, 2001, pp. 1279-1287.
[28] T. Naoe, K. Takeyama, T. Yokozawa, H. Kiyoi, et al., “Analysis of Genetic Polymorphism in NQ01, GSTM-1, GST-T1, and CYP3A4 in 469 Japanese Patients with Therapy-Related Leukemia Mielodysplasic Syndrome and de Novo Acute Myeloid Leukemia,” Clinical Cancer Research, Vol. 6, No. 10, 2000, pp. 4091-4095.
[29] B. Ambrosone, C. Sweeney, B. F. Coles, P. A. Thompson, G. Y. McClure, S. Korourian, M. Y. Fares, A. Stone, F. F. Kadlubar and L. F. Hutchins, “Polymorphisms in Glutathione S-Transferase (GSTM1 and GSTT1) and Survival after Treatment for Breast Cancer,” Cancer Research, Vol. 61, 2001, pp. 7130-7135.
[30] A. Hiroven, “Polymorphisms of Xenobiotic Metabolizing Enzymes and Susceptibility to Cancer,” Environmental Health Perspectives, Vol. 107, No. 1, 1999, pp. 37-47.
[31] W. W. Au, H. Y. Oh, J. Grady, S. A. Salama and M. Y. Heo, “Usefulness of Genetic Susceptibility and Biomarkers for Evaluation of Environmental Health Risk,” Environmental and Molecular Mutagenesis, Vol. 37, No. 3, 2001, pp. 215-225. doi:10.1002/em.1030
[32] M. Saadat, “Genetic Polymorphisms of Glutathione S-Transferase T1 (GSTT1) and Susceptibility to Gastric Cancer: A Meta-Analysis,” Cancer Science, Vol. 97, No. 6, 2006, pp. 505-509.
[33] K. M. Kelly and J. P. Perentesis, “Polymorphisms of Drug Metabolizing Enzymes and Markers of Genotoxicity to Identify Patients with Hodgkin’s Lymphoma at Risk of Treatment-Related Complications,” Annals of Oncology, Vol. 13, No. 1, 2002, pp. 34-39.
[34] D. Sheenan, G. Meade, V. M. Foley and C. A. Dowd, “Structure, Function and Evolution of Glutathione Transferases: Implications for CLassification of Non-Mammalian Members of an Ancient Enzyme Superfamily,” Biochemical Journal, Vol. 360, 2001, pp. 1-16. doi:10.1042/0264-6021:3600001
[35] L. Jiao, M. L. Bondy, M. M. Hassan, D. Z. Chang, J. L. Abbruzzese, D. B. Evans, M. H. Smolensky and D. Li, “Glutathione S-Transferase Gene Polymorphism and Risk and Survival of Pancreatic Cancer,” Cancer, Vol. 109, No. 5, 2007, pp. 840-848. doi:10.1002/cncr.22468
[36] M. Habdous, G. Siest, B. Herbeth, M. Vicent-Viry and S. Visvikis, “Polymorphismes des Glutathionne S-Transférases et Pathologies Humaines: Bilan des études épidémiologiques,” Annals of Biology, Vol. 62, 2004, pp. 15-24.
[37] Valladares, N. García Hernández, F. Salamanca Gómez, E. Curiel Quesada, E. Madrigal Bujaidar, M. D. Vergara, M. Sierra Martinez and D. Arenas Arana, “Genetic Expression Profiles and ChromoSomal Alterations in Sporadic Breast Cáncer in Mexican Women,” Cancer Genetics and Cytogenetics, Vol. 170, No. 2, 2006, pp. 147-151. doi:10.1016/j.cancergencyto.2006.06.002
[38] A. Insan, I. Chirivella and A. Llunch, “Tratamiento Neoadyuvante del Cáncer de Mama Operable,” Medicine Clinic, Vol. 126, No. 8, 2006, pp. 295-303.
[39] Apendice F. Declaracion de Helsinki. [].
[40] S. Z. Abdel-Rahman, R. A. El-Zein, W. A. Anwar, et al., “A multiplex PCR Procedure for Polymorphic Analysis of GSTM1 and GSTT1 Genes in Population Studies,” Cancer Letters, Vol. 107, No. 2, 1996, pp. 229-233. doi:10.1016/0304-3835(96)04832-X
[41] G. van der Zee, B. van Ommen, C. Meijer, H. Hollema, P. J. van Bladeren and E. G. de Vries, “Glutathione S-Transferase Activity and Isoenzyme Composition in Benign Ovarian TUmurs, Untreated Malignant Ovarian Tumours, and Malignant Ovarian Tumours after Platinum/Cyclophosphamide Chemotherapy,” British Journal of Cancer, Vol. 66, No. 5, 1992, pp. 930-936. doi:10.1038/bjc.1992.388
[42] S. Zhong, M. Huang, X. Yang, L. Liang, Y. Wang, M. Romkes, W. Duan, E. Chan and S. F. Zhou, “Relationship of Glutathione S-Transferase Genotypes with Side-Effects of Pulsed Cyclophosphamide Therapy in Patients with Systemic Lupus Erythematosus,” British Journal of Clinical Pharmacology, Vol. 62, No. 4, 2006, pp. 457-472. doi:10.1111/j.1365-2125.2006.02690.x
[43] Howells, C. W. Redman, K. K. Dhar, P. Sarhanis, C. Musgrove, P. W. Jones, J. Alldersea, A. A. Fryer, P. R. Hoban and R. C. Strange, “Association of Glutathione S-Transferase GSTM1 and GSTT1 Null Genotypes with Clinical Outcome in Epithelial Ovarian Cancer,” Clinical Cancer Research, Vol. 4, No. 10, 1998, pp. 2439-2445.
[44] S. Lizard Nacol, B. Coudert, P. Colosetti, J. M. Riedinger, P. Fargeot and P. Brunet-Lecomte, “Glutathione S- Transferse M1 Null Genotype: Lack of Association with Tumor Characteristics and Survival Advanced Breast Cancer,” Breast Cancer Research, Vol. 1, No. 1, pp. 81-87. doi:10.1186/bcr17
[45] P. P. Gor, H. I. Su, R. J. Gray, P. A. Gimotty, M. Horn, R. Aplenc, W. P. Vaughan, M. S. Tallman, T. R. Rebbeck and A. DeMichele, “CyclophosPhamide-Metabolizing Enzyme Polymorphisms and Survival Outcomes after Adjuvant Chemotherapy for Node-Positive Breast Cancer: A Retrospective Cohort Study,” Breast Cancer Research, Vol. 12, 2010. doi:10.1186/bcr2570
[46] R. Pérez, C. Castro, M. E. Gonsebatt and J. Rubio, “Polymorphisms of CYP1A1*2C, GSTM1*0 and GSTT1*0 in Mexican Mestizo Population: A Similitude Analysis,” Human Biology, Vol. 80, No. 4, 2008, pp. 457-465.
[47] J. Zapata Castilla, E. Recinos Money, M. Cuéllar Hubbe, C. D. Robles Vidal and E. Maafs Molina, “Clasificación Molecular del Cáncer de Mama,” Cir Ciruj, Vol. 76, 2008, pp. 87-93.

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