Mitochondrial uncoupling proteins (UCPs) are nuclear-encoded mitochondrial membrane transporters involved in energy metabolism. UCP2 and UCP3 are located adjacent to each other on chromosome 11in a region linked to hyperinsulinemia and obesity. The physiological roles of UCP2 and UCP3 are not completely understood, but there is growing support for the role of UCP2 in the regulation of mitochondrial reactive oxygen species (ROS). Obesity and diabetes have been causally associated with hyperglycemia-induced production of ROS. Elevated cellular ROS has been implicated in the etiology of several human diseases, and recent studies have supported a role for ROS in breast cancer risk. Preliminary studies from our laboratory show over-expression of UCP2 protein in breast tumors, lending support to the hypothesis that expression levels could impact response to therapy.

Genetic variants have been described in the UCP2 gene that influences cellular levels of mRNA. A functional single nucleotide polymorphism (SNP) in the promoter region of the UCP2 gene (-866 G/A) results in increased protein expression for individuals with the A variant. This SNP has been associated with leptin resistance, diabetes mellitus and body weight regulation. There is also a 45-bp insertion polymorphism (INDEL) in the 3’ untranslated region of exon 8 that is believed to alter mRNA stability. We examined the association of these SNPs with anthropomorphic measures (waist-to-hip ratio and body mass index) in a population of 288 healthy Caucasian women. The -866 G/A SNP was associated with both waist-to-hip ratio (p=0.04) and body mass index (p=0.057). The INDEL was also associated with both these parameters (p=0.002 and p=0.032, respectively). Neither SNP was associated with age or menopausal status.

When these genetic variants were examined in a pilot study of breast cancer (cases = 173 and controls =131), we found no main effect of genotype with breast cancer risk. However, there was an interaction between the genetic variants, waist-to-hip ratio and increased breast cancer risk (OR=1.93, 95% CI 0.94-2.39 for -866 G/A SNP and OR=1.87, 95% CI 1.07-3.36).

Taken together, these studies suggest a role for genetic variability in UCP2 in both breast cancer risk and prognosis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA