PHENOTYPIC FEATURES OF BREAST-CANCER CELLS OVEREXPRESSING ORNITHINE-DECARBOXYLASE

Polyamines (PA) have been shown to be critical mediators of estradiol- induced breast cancer cell proliferation. This finding suggests that c onstitutive activation of the PA pathway may promote tumor progression , possibly leading to hormone independence. To test this hypothesis, w e transfected hormone-responsive MCF-7 breast cancer cells with a comp lementary DNA coding for ornithine-decarboxylase (ODC), the first rate -limiting enzyme in PA biosynthesis. Marked ODC overexpression observe d in stably transfected clones was associated with a selective increas e in cellular putrescine content, while spermidine and spermine levels were not altered. ODC-overexpressing MCF-7 cells were resistant to th e antiproliferative effects of low but not high concentrations of the enzyme inhibitor, alpha-difluoromethylornithine. In agreement with our hypothesis, sensitivity to the growth-promoting action of estradiol w as reduced by approximately one third (P < 0.001) in ODC-overexpressin g MCF-7 cells compared with vector-only transfected clones. Basal grow th under anchorage-dependent conditions was only marginally increased by ODC overexpression (P = 0.048), while clonogenicity in soft agar wa s actually reduced. These data suggest that activation of PA biosynthe sis may contribute in part to the acquisition of estrogen independence by breast cancer cells. Since only putrescine content was increased a s a result of ODC overexpression, these data may underestimate the ove rall influence of the PA pathway on breast cancer phenotype. (C) 1995 Wiley-Liss, Inc.