CYSTIC-FIBROSIS HETEROZYGOSITY AND HOMOZYGOSITY IS ASSOCIATED WITH INHIBITION OF BREAST-CANCER GROWTH

Cystic fibrosis (CF) is the most common lethal recessive genetic disea se of the Caucasian population. Although reports of cancer frequency i n CF have emphasized an elevated observed-to-expected ratio of 6.5 for digestive tract cancers, these studies also show a significantly decr eased observed-to-expected ratio for other malignancies including brea st cancer. The cystic fibrosis transmembrane conductance regulator (CF TR) functions as an ATP channel(1-3). We found that heterozygous and h omozygous CFTR knockout mice had elevated blood ATP concentrations. El evated extracellular ATP is known to inhibit tumor growth in vivo and in vitro(4-7). Using double mutant mice created by F-2 generation cros ses of CFTR knockout and nude mice, we observed reduced breast tumor i mplantability in CFTR homozygous nude animals. Decreased tumor growth rate was observed in both CFTR heterozygous and homozygous nude animal s. Extracellular ATP reduced human tumor cell growth rate in vitro, an d a breast transfected with human CFTR that had high extracellular ATP concentrations in vitro correspondingly had a slower growth rate in v ivo. The results suggest that both CFTR heterozygosity and homozygosit y suppress breast cancer growth and that elevated extracellular ATP ca n account for this phenomenon.