Endocrinology, Vol 132, 179-185, Copyright © 1993 by Endocrine Society

ARTICLES

Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells

P Couture, C Theriault, J Simard and F Labrie
Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada.

The estrogen-sensitive human breast cancer cell line ZR-75-1 was used to study the regulation of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD), the enzyme responsible for the interconversion of estrone (E1) and estradiol (E2). We, thus, investigated the effects of a 6-day exposure to various steroids or growth factors on the reductive (E1-- >E2) and oxidative (E2-->E1) 17 beta HSD activities in ZR-75-1 cells as measured during a subsequent 16-h incubation with [3H]E1 or [3H]E2. The reductive 17 beta HSD activity was approximately 3-fold higher than the corresponding oxidative (E2-->E1) activity in control cells, thus favoring the predominance of E2 within the cell. Exposure to dihydrotestosterone (DHT) increased by 1.4-fold the reductive 17 beta HSD activity, with the stimulatory effect exerted at an EC50 value of 0.09 nM DHT, while the oxidative pathway was increased by 4.15-fold at an EC50 value of 0.17 nM. Incubation with medroxyprogesterone acetate, on the other hand, enhanced reductive 17 beta HSD activity by 1.87- fold, while the same treatment increased oxidative 17 beta HSD activity by 2.85-fold; the effects were exerted at EC50 values of 0.4 and 5 nM, respectively. The stimulatory effect of both steroids on 17 beta HSD activity was almost completely reversed by simultaneous exposure to the pure antiandrogen hydroxyflutamide (3 microM), thus supporting an action exerted through the androgen receptor. On the other hand, the synthetic estrogen ethynyl estradiol (EE2) inhibited the reductive and oxidative 17 beta HSD activities by 40% and 33%, respectively, whereas dexamethasone (300 nM) increased by 2.5- and 1.9-fold the reductive and oxidative 17 beta HSD activities, respectively. The present data showing that DHT and the androgenic compound medroxyprogesterone acetate favor the degradation of E2 into E1 suggest that the potent antiproliferative activity of these two compounds in E2-stimulated ZR- 75-1 human breast cancer cells could be at least partially exerted through changes in 17 beta HSD activity.

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