A role for allelic variation within the gene for the
antioxidant selenoprotein glutathione peroxidase 1 (GPx-1) in the risk or etiology of
breast cancer was investigated. By analyzing the frequency of a polymorphism within the GPx-1 gene resulting in a
leucine or
proline at
codon 198, it was determined that the
leucine-containing allele was more frequently associated with
breast cancer than the
proline-containing allele (odds ratio = 1.9; P < 0.05). However, the heterozygosity index for this polymorphism was lower in the
breast cancer samples. To determine whether this was because of the loss of heterozygosity (LOH) during
tumor development, another polymorphic marker within GPx-1, which is frequently heterozygous in the human population, was analyzed. These studies indicated that LOH at this locus is a frequent event, occurring in approximately 36% of the
breast tumor DNAs analyzed. The consequences of the identity of the
amino acid at position 198 were investigated by engineering
breast carcinoma cells that exclusively express either the
leucine- or
proline-containing GPx-1 allele and studying the response to increasing concentrations of
selenium. These studies indicated that the
leucine-containing allele was less responsive to the stimulation of GPx-1
enzyme activity observed during
selenium supplementation than the allele differing only by a
proline at that position. These studies support a role for GPx-1 allelic identity and LOH as factors of significance to
breast cancer development.