EFFECTS OF 2 CLASSES OF PROGESTAGENS, PREGNANE AND 19-NORTESTOSTERONEDERIVATIVES, ON CELL-GROWTH OF HUMAN BREAST-TUMOR CELLS .2. T47D CELL-LINES

Two classes of progestagens, e.g. pregnane [Org 2058, progesterone (FR OG), R5020, medroxyprogesterone acetate (MPA)] and 19-nortestosterone derived progestagens [norethisterone (NE), levonorgestrel (LNG), 3-ket odesogestrel (KDG), gestodene (GES), Org 30659] were studied for their effect on cell growth of two human breast tumor T47D cell lines of di fferent origin, i.e. from ATCC (A) and Sutherland (S) et al. [Sutherla nd et al., Cancer Res. 48 (1988) 5084-5091]. The effect of estradiol ( E(2)) and progestagens alone as well as the combined effect of E(2) (1 0(-10) M) and progestagens were investigated at several dose levels. C ompared with E(2)-induced growth at 10(-10) M, pregnane and 19-nortest osterone derived progestagens at 10(-6) M alone did enhance cell growt h in T47D-A cells up to 25 and 100% respectively, whereas in T47D-S ce lls they did not influence growth. All these progestagens at 10(-6) M did not affect E(2)-induced growth in T47D-A cells, whereas in T47D-S cells they completely reduced cell proliferation at doses between 10(- 10) and 10(-8) M. The involvement of progestagen (PR) and estrogen (ER ) receptors with respect to growth stimulation was studied by using sp ecific antihormones. In T47D-A cells, the antiprogestagens RU 38486 an d Org 31710 could not block progestagen-induced growth. Antiestrogens, like 4-hydroxytamoxifen and ICI 164,384, inhibited the 19-nortestoste rone derivative-induced cell growth by approx. 50%. Remarkably, both a ntiprogestagens alone could also inhibit E(2)-induced growth in T47D-A cells by about 50%. In T47D-S cells, E(2)-induced cell growth was com pletely blocked by both antiprogestagens and antiestrogens. Both antip rogestagens in T47D-S cells were equipotent to 4-hydroxytamoxifen and 10-fold more potent than ICI 164,384. In conclusion pregnane and 19-no rtestosterone-derived progestagens stimulated cell growth in T47D-A ce lls at high unphysiological concentrations, whereas they did not affec t cell growth in T47D-S cells. The 19-nortestosterone derivative induc ed growth in T47D-A cells could partially be inhibited by antiestrogen s. In T47D-A cells, E(2)-induced cell growth was not influenced by bot h classes of progestagens, whereas in T47D-S cells all tested progesta gens, antiprogestagens, and antiestrogens inhibited E(2)-induced cell growth completely. These results with T47D cells as well as those obta ined previously with MCF-7 cells show that subclones of cell lines may respond differently to various types of progestagens in the presence and absence of estrogens.