J Breast Cancer.  2012 Jun;15(2):157-161. 10.4048/jbc.2012.15.2.157.

Association of Alanine-Valine Manganese Superoxide Dismutase Gene Polymorphism and Microheterogeneity Manganese Superoxide Dismutase Activity in Breast Cancer and Benign Breast Tissue

• Atoum M
• Abdel-Fattah M
• Nimer N
• Abdel-Rahman S
• Abdeldayem SA

• KMID: 2242185
• DOI: http://doi.org/10.4048/jbc.2012.15.2.157

Abstract

PURPOSE
Although the etiology of breast cancer is multifactorial, oxidative stress plays an important role in carcinogenesis. In this study, manganese superoxide dismutase (MnSOD) gene polymorphism and activity were evaluated in benign and breast cancer tissue.
METHODS
One hundred and one females were enrolled in this study, 65 who were histopathologically diagnosed with breast cancer and 46 who were benign patients. MnSOD enzyme activity was determined using an indirect competitive inhibition assay and MnSOD gene polymorphism using poly merase chain reaction and agarose gel electrophoresis.
RESULTS
MnSOD enzymatic activity (79.83+/-42.14) was lower in breast cancer tissue compared to benign tumors (236.18+/-46.37). At the same time, MnSOD enzymatic activity among Ala/Val patients was significantly lower in breast cancer tissue (39.19+/-7.33) than in Val/Val malignant breast tumors tissue (96.9+/-22.9). MnSOD enzymatic activity was significantly lower in Val/Val cancer tissue (96.9+/-22.9) than in benign tissue (255.44+/-42.7).
CONCLUSION
Breast cancer tumors contain less MnSOD than benign breast samples. Patients with Ala/Val polymorphism had reduced MnSOD activity compared to patients with Val/Val breast cancer. Ala/Val gene polymorphism may be a risk factor associated with more advanced breast cancer stage. MnSOD gene polymorphism Ala/Val may be a risk factor associated with more advanced breast cancer stage, and reduction of MnSOD activity may be a mechanism of the progression of benign to malignant tumors. Further investigations are needed to evaluate the role of MnSOD in breast cancer progression.

Keyword

Benign; Breast; Cancer; MnSOD; Polymorphism

MeSH Terms

Breast
Breast Neoplasms
Female
Humans
Manganese
Oxidative Stress
Risk Factors
Sepharose
Superoxide Dismutase
Manganese
Sepharose
Superoxide Dismutase

Reference

1. Holley AK, Dhar SK, Xu Y, St Clair DK. Manganese superoxide dismutase: beyond life and death. Amino Acids. 2012. 42:139–158.

2. Gago-Dominguez M, Jiang X, Castelao JE. Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res. 2007. 9:201.

3. Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog. 2006. 5:14.

4. Cook JA, Gius D, Wink DA, Krishna MC, Russo A, Mitchell JB. Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol. 2004. 14:259–266.

5. Wang LI, Miller DP, Sai Y, Liu G, Su L, Wain JC, et al. Manganese superoxide dismutase alanine-to-valine polymorphism at codon 16 and lung cancer risk. J Natl Cancer Inst. 2001. 93:1818–1821.

6. Mitrunen K, Sillanpää P, Kataja V, Eskelinen M, Kosma VM, Benhamou S, et al. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis. 2001. 22:827–829.

7. Millikan RC, Player J, de Cotret AR, Moorman P, Pittman G, Vannappagari V, et al. Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African Americans and whites. Breast Cancer Res. 2004. 6:R264–R274.

8. Cai Q, Shu XO, Wen W, Cheng JR, Dai Q, Gao YT, et al. Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Breast Cancer Res. 2004. 6:R647–R655.

9. Mukhopadhyay S, Das SK, Mukherjee S. Expression of Mn-superoxide dismutase gene in nontumorigenic and tumorigenic human mammary epithelial cells. J Biomed Biotechnol. 2004. 2004:195–202.

10. Negahdar M, Djalali M, Abtahi H, Sadeghi MR, Aghvami T, Javadi E, et al. Blood superoxide dismutase and catalase activities in women affected with breast cancer. Iran J Public Health. 2005. 34:39–43.

11. Amstad PA, Liu H, Ichimiya M, Berezesky IK, Trump BF. Manganese superoxide dismutase expression inhibits soft agar growth in JB6 clone41 mouse epidermal cells. Carcinogenesis. 1997. 18:479–484.

12. Lam EW, Zwacka R, Seftor EA, Nieva DR, Davidson BL, Engelhardt JF, et al. Effects of antioxidant enzyme overexpression on the invasive phenotype of hamster cheek pouch carcinoma cells. Free Radic Biol Med. 1999. 27:572–579.

13. Li JJ, Colburn NH, Oberley LW. Maspin gene expression in tumor suppression induced by overexpressing manganese-containing superoxide dismutase cDNA in human breast cancer cells. Carcinogenesis. 1998. 19:833–839.

14. Oberley LW, Oberley TD. Massaro D, Clerch LB, editors. Role of antioxidant enzymes in the cancer phenotype. Oxygen, Gene Expression, and Cellular Function. 1997. New York: M. Dekker;279–307.

15. Zhao Y, Chaiswing L, Velez JM, Batinic-Haberle I, Colburn NH, Oberley TD, et al. p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. Cancer Res. 2005. 65:3745–3750.

16. Rosenblum JS, Gilula NB, Lerner RA. On signal sequence polymorphisms and diseases of distribution. Proc Natl Acad Sci U S A. 1996. 93:4471–4473.

17. Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-Hattori Y, Shimizu Y, Mizuno Y. Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochem Biophys Res Commun. 1996. 226:561–565.

18. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics. 2003. 13:145–157.

19. Qiu LX, Yao L, Mao C, Chen B, Zhan P, Yuan H, et al. Lack of associa tion between MnSOD Val16Ala polymorphism and breast cancer risk: a meta-analysis involving 58,448 subjects. Breast Cancer Res Treat. 2010. 123:543–547.

20. Eras-Erdogan N, Akbas E, Senli H, Kul S, Colak T. Relationship between polymorphism in the manganese superoxide dismutase gene and breast cancer. Mutat Res. 2009. 680:7–11.

21. Atoum MF, Hourani HM, Shoter A, Al-Raheem SN, Al Muhrib TK. TNM staging and classification (familial and nonfamilial) of breast cancer in Jordanian females. Indian J Cancer. 2010. 47:194–198.

22. Spitz DR, Oberley LW. An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal Biochem. 1989. 179:8–18.

23. Tamimi RM, Hankinson SE, Spiegelman D, Colditz GA, Hunter DJ. Manganese superoxide dismutase polymorphism, plasma antioxidants, cigarette smoking, and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2004. 13:989–996.

24. Sun GG, Wang YD, Chen LQ, Wang SJ, Liu GL, Yu XR, et al. Novel cancer suppressor gene for esophageal cancer: manganese superoxide dismutase. Dis Esophagus. In press.

25. Park CK, Jung JH, Moon MJ, Kim YY, Kim JH, Park SH, et al. Tissue expression of manganese superoxide dismutase is a candidate prognostic marker for glioblastoma. Oncology. 2009. 77:178–181.

26. Baker AM, Oberley LW, Cohen MB. Expression of antioxidant enzymes in human prostatic adenocarcinoma. Prostate. 1997. 32:229–233.

27. Hitchler MJ, Oberley LW, Domann FE. Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells. Free Radic Biol Med. 2008. 45:1573–1580.

28. Bag A, Bag N. Target sequence polymorphism of human manganese superoxide dismutase gene and its association with cancer risk: a review. Cancer Epidemiol Biomarkers Prev. 2008. 17:3298–3305.

29. Kucukgergin C, Sanli O, Tefik T, Aydin M, Ozcan F, Seckin S. Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism. Mol Biol Rep. 2012. 39:193–198.