Effects of two classes of progestagens, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: II. T47D cell lines.
Two classes of progestagens, e.g. pregnane [Org 2058, progesterone (PROG), R5020, medroxyprogesterone acetate (MPA)] and 19-nortestosterone derived progestagens [norethisterone (NE), levonorgestrel (LNG), 3-ketodesogestrel (KDG), gestodene (GES), Org 30659] were studied for their effect on cell growth of two human breast tumor T47D cell lines of different origin, i.e. from ATCC (A) and Sutherland (S) et al. [Sutherland et al., Cancer Res. 48 (1988) 5084-5091]. The effect of estradiol (E2) and progestagens alone as well as the combined effect of E2 (10(-10) M) and progestagens were investigated at several dose levels. Compared with E2-induced growth at 10(-10) M, pregnane and 19-nortestosterone derived progestagens at 10(-6) M alone did enhance cell growth in T47D-A cells up to 25 and 100% respectively, whereas in T47D-S cells they did not influence growth. All these progestagens at 10(-6) M did not affect E2-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 specific antihormones. In T47D-A cells, the antiprogestagens RU 38486 and Org 31710 could not block progestagen-induced growth. Antiestrogens, like 4-hydroxytamoxifen and ICI 164,384, inhibited the 19-nortestosterone derivative-induced cell growth by approx. 50%. Remarkably, both antiprogestagens alone could also inhibit E2-induced growth in T47D-A cells by about 50%. In T47D-S cells, E2-induced cell growth was completely blocked by both antiprogestagens and antiestrogens. Both antiprogestagens in T47D-S cells were equipotent to 4-hydroxytamoxifen and 10-fold more potent than ICI 164,384. In conclusion pregnane and 19-nortestosterone-derived progestagens stimulated cell growth in T47D-A cells at high unphysiological concentrations, whereas they did not affect cell growth in T47D-S cells. The 19-nortestosterone derivative induced growth in T47D-A cells could partially be inhibited by antiestrogens. In T47D-A cells, E2-induced cell growth was not influenced by both classes of progestagens, whereas in T47D-S cells all tested progestagens, antiprogestagens, and antiestrogens inhibited E2-induced cell growth completely. These results with T47D cells as well as those obtained 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.
Schoonen
W G
WG
Department of Endocrinology, N.V. Organon, Oss, The Netherlands.
Joosten
J W
JW
Kloosterboer
H J
HJ
D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017135:Desogestrel / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D016912:Levonorgestrel / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009640:Norethindrone / Q000031:analogs & derivatives / Q000494:pharmacology; D009652:Norpregnenes / Q000494:pharmacology; D011278:Pregnanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011397:Promegestone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004963:Estrenes; D004965:Estrogen Antagonists; D005663:Furans; D009652:Norpregnenes; D011278:Pregnanes; D011282:Pregnenediones; C076196:Org 31710; C033273:Gestodene; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; C044815:etonogestrel; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D016912:Levonorgestrel; D009277:Nandrolone; D017135:Desogestrel; D011397:Promegestone; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone; C097629:Org 30659