cell biochemistry and function Cell Biochem Funct 2005; 23: 73–76. Published online 19 July 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1027/cbf.1128 SHORT COMMUNICATION Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility Neslihan Aygu ¨n Kocabas ¸* 1 , Semra S ¸ardas ¸ 1 , Suzanne Cholerton 2 , Ann K. Daly 2 , Atilla H. Elhan 3 and Ali Esat Karakaya 1 1 Department of Toxicology, University of Gazi, Pharmacy Faculty, Ankara,Turkey 2 Department of Pharmacological Sciences, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK 3 Department of Biostatistics, University of Ankara, Medical Faculty, Ankara, Turkey Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case–control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymer- ase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no sig- nificant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI) 0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for devel- oping breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m 2 (OR: 1.42 (95%CI ¼ 1.04–1.93)). Copyright # 2004 John Wiley & Sons, Ltd. key words — MnSOD genetic polymorphism; breast cancer; free radical; oestrogen; Turkish population INTRODUCTION There is considerable inter-individual genetic varia- bility in the metabolic and biosynthetic pathways in steroidogenesis. Such variation could explain a por- tion of cancer susceptibility associated with reproduc- tive events and hormone exposure. 1 One potential mechanistic basis for susceptibility factors is through oxidative damage induced by reactive oxygen species (ROS) that has been related to the aetiology of human cancer. 2 ROS are generated by oestrogens and their metabolites, and by a variety of xenobiotics. The accumulation of ROS can damage DNA, proteins and lipids, leading to the initiation or promotion of cancer. 2,3 Superoxide dismutases (SODs) are the first and the most important line of antioxidant enzyme systems against ROS. SOD2, or manganese containing SOD (MnSOD; EC 1.15.1.1), the only known superoxide scavenger in mitochondria, may be particularly important for antioxidant defence. 4 Several, but not all, studies have also emphasised the importance of MnSOD in protection of cells and tissues against hyperoxia, cytokines and possibly cytotoxic drugs, both in vitro and in vivo. 5 Tumour cells over-expressing MnSOD after transfection of the MnSOD gene have been shown to have a lower mitotic rate. The MnSOD gene has therefore been suggested to be a tumour suppressor gene in human breast cancer cells, whereas the signalling pathways induced by cell phenotypic Received 18 September 2003 Revised 21 October 2003 Copyright # 2004 John Wiley & Sons, Ltd. Accepted 23 October 2003 * Correspondence to: Dr N. A. Kocabas ¸, Gazi University, Faculty of Pharmacy, Department of Toxicology, 06330 Hipodrom, Ankara, Turkey. Tel: þ90.312.2123009. Fax: þ90.312.2222326. E-mail: neslihan@gazi.edu.tr