ANTIPROGESTINS INHIBIT GROWTH AND STIMULATE DIFFERENTIATION IN THE NORMAL MAMMARY-GLAND

Antiprogestins possess a potent antitumor activity in hormone-dependen t experimental breast cancer models. Though the underlying mechanism i s not clear, induction of functional differentiation seems to be a maj or event. This study attempts to test directly for antiproliferative a nd differentiation promoting activities of antiprogestins on the norma l mammary gland. To this end, whole organ cultures of mammary glands f rom estradiol/progesterone-primed virgin mice maintained in a serum-fr ee medium with aldosterone, prolactin, insulin, and hydrocortisone wer e exposed to the antiprogestin ZK114043. A 4-day treatment of organ cu ltures led to a strong inhibition of epithelial DNA synthesis. In para llel, ZK114043 caused alveolar cells to acquire a more differentiated phenotype distinguished by secretory active alveoli composed of single cell layers with increased fat droplet accumulation and enhanced expr ession of the milk proteins beta-casein and whey acidic protein (WAP). Particularly strong effects were found on the expression of mammary-d erived growth inhibitor (MDGI). Both half-maximal inhibition of epithe lial DNA synthesis and stimulation of MDGI mRNA expression were found at about 5 ng/ml of ZK114043. Presence in the medium of 5 mu g/ml hydr ocortisone rendered antiglucocorticoid effects of ZK114043 highly unli kely. Furthermore, prevention of action of ZK114043 by the progesteron e agonist R5020 and ZK114043 stimulated expression of beta-casein and MDGI mRNA in cultured glands of 10-week-old unprimed virgin mice sugge st a progesterone receptor-mediated mechanism of antiprogestin action. Two other antiprogestins, Mifepristone and Onapristone, likewise stim ulated MDGI expression. The data provide direct evidence that antiprog estins act like a differentiation factor in the normal mammary gland. (C) 1995 Wiley-Liss, Inc.