ANDROGEN-LIKE AND ANTI-ANDROGEN-LIKE EFFECTS OF ANTIPROGESTINS IN HUMAN MAMMARY-CANCER CELLS

In addition to their antiprogestational activity, the antiprogestins R U486, ZK98.299 and ZK98.734 possess varying antiglucocorticoid as well as androgen-like or antiandrogen-like properties in human mammary can cer cells. The human mammary cancer cell line MFM-223, which contains only androgen receptors, was used as a model to investigate androgen r eceptor mediated effects of these antiprogestins. Proliferation of MFM -223 cells is inhibited by androgens and does not respond to oestrogen s, progestins and glucocorticoids. As shown in proliferation assays, Z K98.734 was a strong inhibitor of cell proliferation. This effect was antagonised by the antiandrogen hydroxyflutamide. ZK98.734 was found t o displace [H-3]R1881 from the androgen receptor in MFM-223 cells, sub stantiating the involvement of the androgen receptor. The antiprogesti n ZK98.299 failed to influence the proliferation of MFM-223 cells. ZK9 8.299 did not bind to the androgen receptor and was devoid of androgen ic or antiandrogenic activity. RU486 bound to the androgen receptor. I t was a weak inhibitor of MFM-223 cell proliferation, but the inhibiti on of proliferation by RU486 was not antagonised by hydroxyflutamide. This effect was probably not mediated by the androgen receptor. RU486 had antiandrogenic activity in this cell line, as it antagonised the i nhibitory effect of dihydrotestosterone at a 100-molar excess. These r esults were confirmed by transfection experiments with an MMTV-CAT con struct in the same cell line, demonstrating the biological function of the ZK98.734-androgen receptor complex. ZK98.299 and RU486 were not a ble to induce CAT activity. The different androgenic or antiandrogenic properties of the antiprogestins investigated should be considered wh en selecting antiprogestational compounds for clinical applications, a s a partial androgenic activity may be of benefit in breast cancer but can have undesired side-effects in other diseases. (C) 1996 Elsevier Science Ltd