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

Medical Research Council Group in Molecular Endocrinology, CHUL Research Centre and Laval University, Quebec, G1V 4G2, Canada

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.

¹ This research was supported in part by the Medical Research Council of Canada (Group in Molecular Endocrinology) (J. S. and F. L.), the Fonds de la Recherche en Santé du Québec, and Endorecherche.

² Holder of a postdoctoral fellowship from Medical Research Council-Canada.

³ Holder of a studentship from the Ministère de la Recherche et de l'Enseignement Supérieur de France.

⁴ Holder of a scholarship from Medical Research Council-Canada.

⁵ To whom requests for reprints should be addressed.

Received 11/ 9/90. Accepted 3/19/91.

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