Inhibition of cell cycle kinetics and proliferation by the androgen 5 alpha-dihydrotestosterone and antiestrogen N,n-butyl-N-methyl-11-[16' alpha-chloro-3',17 beta-dihydroxy-estra-1',3',5'-(10')triene-7' alpha-yl] undecanamide in human breast cancer ZR-75-1 cells.
We have investigated the effects of the pure antiestrogen EM-139 and the nonaromatizable androgen dihydrotestosterone (DHT) alone or in combination with estradiol (E2) on cell proliferation and cell kinetic parameters in human ZR-75-1 breast cancer cells. Following a 24- to 30-h exposure to E2, a decrease in the proportion of G0-G1 cells was observed, this effect being accompanied by the well-known stimulatory effect of the estrogen on cell proliferation at later time intervals. By contrast, DHT or EM-139 alone inhibited basal cell proliferation without a significant influence on cell cycle distribution. Moreover, pretreatment with DHT for 8 days, while decreasing ZR-75-1 cell number, did not cause a loss in E2 sensitivity. In fact, as early as after 24 h of E2 treatment, a decrease in the G0-G1 cell fraction accompanied by a corresponding increase of the S-phase was observed in both control and DHT-pretreated cells. When added concomitantly with E2, DHT or EM-139 inhibited the E2 stimulatory effect on cell proliferation, but only EM-139 significantly reversed the G0-G1 decrease induced by E2. Although DHT and EM-139 did not affect the distribution of ZR-75-1 cells between the different phases of the cell cycle, continuous labeling with 5'-bromodeoxyuridine showed that EM-139 and DHT had a global slowing effect on the duration of the cell cycle, thus explaining the potent inhibitory effect of these compounds on cell proliferation. The present data demonstrate that DHT and EM-139 are both potent inhibitors of the stimulatory effect on E2 on cell proliferation, their main action being related to a general increase in the duration of the cell cycle.
de Launoit
Y
Y
Medical Research Council Group in Molecular Endocrinology, CHUL Research Centre, Quebec, Canada.
Dauvois
S
S
Dufour
M
M
Simard
J
J
Labrie
F
F
D001943:Breast Neoplasms / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007399:Interphase / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D013196:Dihydrotestosterone; C064480:EM 139; D004958:Estradiol; D001973:Bromodeoxyuridine