Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer

Oxidative stress, resulting from the imbalance between prooxidant and antio xidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of ant ioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substi tution that seems to alter transport of the enzyme into the mitochondrion. changing its efficacy in fighting oxidative stress, was associated with bre ast cancer risk and that a diet rich in sources of antioxidants could ameli orate the effects on risk. Data were collected in a case-control study of d iet and breast cancer in western New York from 1986 to 1991. Caucasian wome n with incident, primary, histologically confirmed breast cancer were frequ ency-matched on age and county of residence to community controls. Blood sp ecimens were collected and processed from a subset of participants in the s tudy (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk, We also evaluated the effect of the polymorphism on risk among low and high consumers of Fruits and vegetables. Premenopausal women who w ere homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confide nce interval, 1.7-10.8). Risk was most pronounced among women below the med ian consumption of fruits and vegetables and of dietary ascorbic acid and c u-tocopherol, with little increased risk for those with diets rich in these foods, Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (od ds ratio, 1.8; confidence interval, 0.9-3.6), No appreciable modification o f risk by diet was detected for these older women. These data support the h ypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women, The finding that risk wa s greatest among women who consumed lo rc er amounts of dietary antioxidant s and was minimal among high consumers indicates that a diet rich in source s of antioxidants may minimize the deleterious effects of the MnSOD polymor phism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against can cer.