Progestin regulation of 11beta-hydroxysteroid dehydrogenase expression in T-47D human breast cancer cells.
This study examined the enzymatic characteristics and steroid regulation of the glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in the human breast cancer cell line T-47D. In cell homogenates, exogenous NAD significantly increased the conversion of corticosterone to 11-dehydrocorticosterone, while NADP was ineffective. There was no conversion of 11-dehydrocorticosterone to corticosterone either with NADH or NADPH demonstrating the lack of reductase activity. In keeping with these results, RT-PCR analysis indicated a mRNA for 11beta-HSD2 in T-47D cells, while 11beta-HSD1 mRNA levels were undetectable. In T-47D cells treated for 24 h with medroxyprogesterone acetate (MPA), 11beta-HSD catalytic activity was elevated 11-fold, while estrone (E(1)), estradiol (E(2)) and the synthetic glucocorticoid dexamethasone (DEX) were ineffective. The antiprogestin mifepristone (RU486) acted as a pure antagonist of the progestin-enhanced 11beta-HSD activity, but did not exert any agonistic effects of its own. In addition, RT-PCR analysis demonstrated that MPA was a potent inducer of 11beta-HSD2 gene expression, increasing the steady-state levels of 11beta-HSD2 mRNA. Taken together, these results demonstrate that 11beta-HSD2 is the 11beta-HSD isoform expressed by T-47D cells under steady-state conditions and suggest the existence of a previously undocumented mechanism of action of progestins in breast cancer cells.
Arcuri
F
F
Institute of Pathological Anatomy, University of Siena, Italy. arcuri@unisi.it
Sestini
S
S
Ricci
C
C
Runci
Y
Y
Carducci
A
A
Paulesu
L
L
Cintorino
M
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004970:Estrone / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D045167:Progesterone Congeners / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D014407:Tumor Cells, Cultured
D045167:Progesterone Congeners; D011372:Progestins; D012333:RNA, Messenger; D009243:NAD; D004970:Estrone; D015735:Mifepristone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; C003552:11-dehydrocorticosterone; D003345:Corticosterone