Estrogen-stimulated glucuronidation of dihydrotestosterone in MCF-7 human breast cancer cells.
The non-aromatizable androgen dihydrotestosterone (DHT) has been shown to exert a potent inhibitory effect on the proliferation of some human breast cancer cell lines. DHT, however, has little or no significant inhibition on MCF-7 cell proliferation in either the presence or absence of estradiol (E2). Since the metabolism of DHT into non-active compounds may be responsible for the observed lack of androgenic effect in this cell line, we have investigated the metabolic fate of labeled DHT in MCF-7 cells. A time course incubation was performed with 1 nM [3H]DHT and analysis of the various metabolites formed revealed a time-dependent increase in glucuronidated steroids which was stimulated more than 4-fold by 0.1 nM E2. The major glucuronidated steroid was androstane-3 alpha, 17 beta-diol in both control and E2-stimulated cells, comprising 22 +/- 1.2% and 30 +/- 0.6% of the total radioactivity in the medium, respectively. Other steroid glucuronides observed included DHT, androstane-3 beta,17 beta-diol, and androsterone, all of which were elevated in the E2-treated cells relative to control values. The present data show that E2 exerts a stimulatory effect on the glucuronidation of androgens and their metabolites in the estrogen-dependent breast cancer cell line MCF-7. Since glucuronidation is an effective means of cellular elimination of active steroids, such a pathway may be considered as a possible site of regulation of breast cancer cell growth by hormones.
Roy
R
R
MRC Group in Molecular Endocrinology, CHUL Research Center, Sainte-Foy, Quebec, Canada.
Dauvois
S
S
Labrie
F
F
Belanger
A
A
D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D013196:Dihydrotestosterone / Q000302:isolation & purification / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005965:Glucuronates / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D014316:Tritium
D005965:Glucuronates; D013196:Dihydrotestosterone; D014316:Tritium; D004958:Estradiol