Evaluation of the Relationship between Antioxidant Gene Polymorphisms (Endothelial Nitric Oxide Synthase, Myeloperoxidase, Uncoupling Protein 2) and Breast Cancer
Objectives: This study aimed to determine the relationship of breast cancer development with the polymorphisms of endothelial nitric oxide synthase (eNOS), myeloperoxidase (MPO), and uncoupling protein 2 (UCP2) genes.
Methods: The study included 60 breast cancer patients and 70 healthy controls. After exclusion criteria, 37 patients and 70 healthy controls were enrolled into study. The functional variants studied were intron-4 variable number of tandem repeats (VNTR), -G463A, and -866G/A variants for the eNOS, MPO, and UCP-2 genes, respectively. The polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism (RFLP) methods were used for genotyping. The distribution of genotype frequencies of the eNOS, MPO, and UCP2 genes were compared between the breast cancer patients and healthy controls using the Chi-square test.
Results: The BB genotype of the eNOS gene variant (intron-4 VNTR) was associated with a significantly decreased risk of breast cancer (OR=0.56; 95%CI, 0.463–0.676; p=0.001); the AA and AB genotypes were not associated with the risk of breast cancer as reported in our previous work. No significant association was determined between the risk of breast cancer and any genotype of the MPO gene variant. While the AA (OR=8.167; 95% CI, 2.785–23.951; p=0.001) and AG (OR=4.341; 95% CI, 1.679–11.222; p=0.002) genotypes of the UCP2 gene variant were associated with significantly decreased risk of breast cancer, GG genotype of the UCP2 gene variant was associated with significantly increased risk (OR=5.0; 95% CI, 2.207–11.327; p=0.001).
Conclusion: Outcomes of this study revealed that breast cancer was associated with BB genotype of the intron-4 VNTR variant of the eNOS gene and AA, AG, and GG genotypes of the -866G/A variant of the UCP2.
1. Kelly KM, Shah N, Shedlosky-Shoemaker R, Porter K, Agnese D. Living post treatment: definitions of those with history and no history of cancer. J Cancer Surviv 2011;5:158–66.
2. Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol Biomarkers Prev 2016;25:16–27.
3. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343:78–85.
4. Kehrer JP, Klotz LO. Free radicals and related reactive species as mediators of tissue injury and disease: implications for Health. Crit Rev Toxicol 2015;45:765–98.
5. Steenport M, Eom H, Uezu M, Schneller J, Gupta R, Mustafa Y, et al. Association of polymorphisms in myeloperoxidase and catalase genes with precancerous changes in the gastric mucosa of patients at inner-city hospitals in New York. Oncol Rep 2007;18:235–40.
6. Dosenko VE, Zagoriy VY, Haytovich NV, Gordok OA, Moibenko AA. Allelic polymorphism of endothelial NO-synthase gene and its functional manifestations. Acta Biochim Pol 2006;53:299–302.
7. Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol 2005;77:598–625.
8. Wheatley-Price P, Asomaning K, Reid A, Zhai R, Su L, Zhou W, et al. Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma. Cancer 2008;112:1037–42.
9. Derdák Z, Fülöp P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, et al. Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis 2006;27:956–61.
10. Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G. The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 2008;68:2813–9.
11. Forsberg L, de Faire U, Morgenstern R. Oxidative stress, human genetic variation, and disease. Arch Biochem Biophys 2001;389:84–93.
12. Walch K, Kolbus A, Hefler-Frischmuth K. Polymorphisms of the endothelial nitric oxide synthase gene in premenopausal women with polycystic ovary syndrome. Maturitas 2008;61:256–9.
13. Cascorbi I, Henning S, Brockmöller J, Gephart J, Meisel C, Müller JM, et al. Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant--463A of the myeloperoxidase gene. Cancer Res 2000;60:644–9.
14. Srivastava N, Prakash J, Lakhan R, Agarwal CG, Pant DC, Mittal B. A common polymorphism in the promoter of UCP2 is associated with obesity and hyperinsulenemia in northern Indians. Mol Cell Biochem 2010;337:293–8.
15. Wang X, Axelsson J, Nordfors L, Qureshi AR, Avesani C, Barany P, et al. Changes in fat mass after initiation of maintenance dialysis is influenced by the uncoupling protein 2 exon 8 insertion/deletion polymorphism. Nephrol Dial Transplant 2007;22:196–202.
16. Erdem D, Büyükşimşek M, Günaldı M, Işıksaçan N, Pehlivan S. Evaluation of the Relationship between eNOS and Breast Cancer. Tıp Fakültesi Klinikleri Dergisi 2019;2:23–7.
17. Ahn J, Gammon MD, Santella RM, Gaudet MM, Britton JA, Teitelbaum SL, et al. Myeloperoxidase genotype, fruit and vegetable consumption, and breast cancer risk. Cancer Res 2004;64:7634–9.
18. Lin SC, Chou YC, Wu MH, Wu CC, Lin WY, Yu CP, et al. Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk. Eur J Cancer Prev 2005;14:257–61.
19. Yang J, Ambrosone CB, Hong CC, Ahn J, Rodriguez C, Thun MJ, et al. Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer. Carcinogenesis 2007;28:1247–53.
20. Yang WJ, Wang MY, Pan FZ, Shi C, Cen H. Association between MPO-463G>A polymorphism and cancer risk: evidence from 60 case-control studies. World J Surg Oncol 2017;15:144.
21. Gao X, Wang J, Wang W, Wang M, Zhang J. eNOS Genetic Polymorphisms and Cancer Risk: A Meta-Analysis and a Case-Control Study of Breast Cancer. Medicine (Baltimore) 2015;94:e972.
22. Yao L, Fang F, Zhong Y, Yu L. The association between two polymorphisms of eNOS and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2010;124:223–7.
23. Zhang K, Shang Y, Liao S, Zhang W, Nian H, Liu Y, et al. Uncoupling protein 2 protects testicular germ cells from hyperthermia-induced apoptosis. Biochem Biophys Res Commun 2007;360:327–32.
24. Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K, et al. Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PLoS One 2011;6:e24792.
25. Pons DG, Nadal-Serrano M, Torrens-Mas M, Valle A, Oliver J, Roca P. UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress. Free Radic Biol Med 2015;86:67–77.