Effects of progestins on growth of experimental breast cancer in culture: interaction with estradiol and prolactin and involvement of the polyamine pathway.

The role of progesterone either alone or in combination with other hormones in breast cancer growth is not well established. In these experiments, using the hormone-responsive N-nitrosomethylurea-induced rat mammary tumor grown in the soft agar clonogenic assay, we tested the colony-stimulating effect of progesterone and the synthetic progestin R5020 over a wide range of physiological and pharmacological concentrations (from 0.1 nM to 10 microM). Both progesterone and R5020 were found to have a significant colony-stimulating effect which was more pronounced in the absence of serum. The action of progesterone appeared to plateau at concentrations of 10 or 100 nM, whereas R5020 was maximally effective at lower concentrations (approximately 1 nM). A biphasic dose-dependent effect was occasionally seen both with progesterone and R5020 with a loss of colony-stimulating effect at high concentrations. The combined administration of varying doses of progesterone (0.1, 1, 10, and 100 nM) and estradiol (10(-10) M and 10(-9) M) was found at times to potentiate and at times to decrease colony formation over that observed with the individual treatments. The former effect, when present, was usually seen with low doses of progesterone, while the latter was frequently observed with high concentrations (100 nM). No major potentiation or suppression of colony formation over individual treatments was observed when varying doses of progesterone (1, 10, and 100 nM) were added together with prolactin (50 ng/ml). The administration of the polyamine biosynthesis inhibitor alpha-difluoromethylornithine completely blocked the colony-stimulating effect of progesterone. The inhibitory effect of alpha-difluoromethylornithine was completely reversed in a dose-dependent fashion by exogenous administration of spermidine, thus implying a critical involvement of the polyamine pathway in progesterone action.