Inhibition of Cell Cycle Kinetics and Proliferation by the Androgen 5α-Dihydrotestosterone and Antiestrogen N,n-Butyl-N-methyl-11-[16′α-chloro-3′,17β-dihydroxy-estra-1′,3′,5′-(10′)triene-7′α-yl] Undecanamide in Human Breast Cancer ZR-75-1 Cells¹

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 of E₂ on cell proliferation, their main action being related to a general increase in the duration of the cell cycle.