Human hydroxysteroid (17-beta) dehydrogenase 1 expression enhances estrogen sensitivity of MCF-7 breast cancer cell xenografts.
Hydroxysteroid (17-beta) dehydrogenase 1 (HSD17B1) catalyzes the conversion between estrone (E1) and estradiol (E2). The reaction is reversible in vitro, but the data in cultured cells suggest that E2 production is the predominant reaction in physiological conditions. However, the hypothesis has not been verified in vivo. In the present study, estrogen-dependent MCF-7 human breast cancer cells were stably transfected with an expression plasmid for human HSD17B1. The enzyme efficiently converted E1 to E2 and enhanced the estrogen-dependent growth of cultured MCF-7 cells in the presence of hormonally less active E1. The HSD17B1-expressing cells also formed estrogen-dependent tumors in immunodeficient nude mice. After treating the mice with an appropriate dose of the substrate (E1, 0.1 micromol/kg x d), a marked difference in tumor growth was observed between nontransfected and HSD17B1-transfected MCF-7 cells, mean tumor weights at the end of E1 treatment being 23.2 and 130.4 mg, respectively. Furthermore, estrogen-dependent growth of the HSD17B1-expressing xenografts in the presence of E1 was markedly inhibited by administering 5 micromol/kg x d of a specific HSD17B1 inhibitor. After a 4-wk treatment, the tumor size was reduced by 59.8% as compared with the nontreated tumors, whereas the uterine growth of the mice was not affected by the HSD17B1 inhibitor used. This was in line with the induction of apoptosis of the tumors. The results evidently show that estrogenic response for E1 is enhanced by the local action of HSD17B1 in vivo, and thus, the enzyme is a potential target for pharmacological inhibition of estrogen action.
Husen
Bettina
B
Solvay Pharmaceuticals Research Laboratories, Hans-Böckler-Allee 20, 30173 Hannover, Germany. bettina.husen@solvay.com.
Huhtinen
Kaisa
K
Saloniemi
Taija
T
Messinger
Josef
J
Thole
Hubert H
HH
Poutanen
Matti
M
D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000502:physiology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human