The improved understanding of the genetic modifiers of the determinants of prostate cancer aggressiveness would be beneficial as that knowledge could help identify individuals with increased likelihood of developing life-threatening vs. indolet disease. In the case of polymorphisms within the gene for manganese superoxide dismutase (MnSOD), studies have indicated that the alanine (A) vs. valine (V) variation at codon 16 was associated with increased cancer risk, while other studies were unable to detect that relationship. The discrepancy among these observations may be clarified by the fact that individuals whose genome encode the A-containing MnSOD that partitions more efficiently to the mitochondria experience a 10-fold elevation in aggressive prostate cancer risk that is dependent on their dietary intake of antioxidants, with those in the lowest tertile of antioxidant intake exhibiting the greatest risk. Based on these human epidemiological data, it is proposed that MnSOD exists at the center of an axis of a small number of anti-oxidant molecules that together contribute to the risk of prostate cancer, and perhaps also contribute to determining whether that cancer is of the more dangerous aggressive type.
The first aim of the proposal is to use human prostatic cells in culture to mimic the epidemiological data by manipulating MnSOD and GPx-1 genotype and levels, and determining the consequences to reactive oxygen species generation and damage to biomolecules under controlled experimental conditions. Xenograft studies with human prostate tumor cells engineered to over-express different MnSOD and GPx-1 alleles injected into nude mice will be conducted to evaluate the effect of enhanced levels of these proteins on tumor growth, reactive oxygen levels and cellular oxidative damage.
The third aim will utilize a collection of 400 human prostate samples, half of which came from men whose cancer progressed to aggressive disease and half of which did not in order to determine if MnSOD levels and/or genotype, perhaps in conjunction with GPx-1 and SEPP1 genotype, can be predictive of clinical outcome. It is anticipated that the results of these studies will elucidae some of the important determinants of prostate cancer progression, allowing for better prediction as to whose prostate cancer will progress, and providing new targets for individualized preventive and therapeutic interventions. It is for this reason we consider this a high risk but high reward approach suitable for the R21 mechanism.
Human epidemiology has revealed a remarkable impact of dietary antioxidant intake, as well as polymorphisms in the gene for the GPx-1 anti-oxidant protein, in the risk of aggressive, clinically significant prostate cancer among carriers of a common allelic variant of the MnSOD gene. By studying the mechanism of this interaction in model systems and determining the predictive value of MnSOD allelic identity, novel approaches may be developed to reduce prostate cancer mortality.