POLYAMINE INVOLVEMENT IN BASAL AND ESTRADIOL-STIMULATED INSULIN-LIKE GROWTH-FACTOR I SECRETION AND ACTION IN BREAST-CANCER CELLS IN CULTURE

Recent evidence indicates that the polyamine pathway may play a significant role in the autocrine/paracrine control of breast cancer cell proliferation by hormones. To directly test this hypothesis, in the present experiments, we evaluated the polyamine involvement in immunoactive insulin-like growth factor I (IGF-I) secretion and IGF-I action using MCF-7 breast cancer cells cultured in serum-free medium in the presence and a absence of estradiol (E2). Administration of the polyamine biosynthetic inhibitor, alpha-difluoromethylornithine (DFMO) induced a marked suppression of cellular ornithine decarboxylase (ODC) activity and polyamine levels which was associated with significant, although partial, inhibition of E2-stimulated growth. Exogenous putrescine administration repleted cellular polyamine pools and completely reversed the growth-inhibitory effect of DFMO. Despite these parallel changes in polyamine levels and proliferative activity, basal as well as E2-stimulated levels of immunoactive IGF-I measured in the conditioned media were unaffected by DFMO with and without exogenous putrescine administration. On the other hand, induction of polyamine depletion and repletion by the same treatments significantly (although partially) affected the proliferative action of exogenously added IGF-I. These findings indicate that polyamines, while not involved in immunoactive IGF-I production, play an important role, at least in part, in IGF-I action in this experimental system. Furthermore, we observed that the administration of a monoclonal antibody directed against IGF-I was able to partially block basal as well as E2-stimulated MCF-7 cell proliferation. We conclude that immunoactive IGF-I is an important but not sole mediator of MCF-7 breast cancer growth under our experimental conditions. The polyamine pathway plays an important role in the expresion of its proliferative action.