Progestin regulation of 11beta-hydroxysteroid dehydrogenase expression in T-47D human breast cancer cells.

Abstract

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.

• Authors: F Arcuri, S Sestini, C Ricci, Y Runci, A Carducci, L Paulesu, M Cintorino
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 72 Issue 5 Pg. 239-47 (Apr 2000) ISSN: 0960-0760 [Print] England
• PMID: 10822013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Progesterone Congeners
• Progestins
• RNA, Messenger
• NAD
• Estrone
• Mifepristone
• Estradiol
• Medroxyprogesterone Acetate
• Hydroxysteroid Dehydrogenases
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• HSD11B1 protein, human
• 11-dehydrocorticosterone
• Corticosterone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Breast Neoplasms (drug therapy, enzymology)
• Carcinoma (drug therapy, enzymology)
• Corticosterone (analogs & derivatives, metabolism)
• Dose-Response Relationship, Drug
• Estradiol (pharmacology)
• Estrone (pharmacology)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Hydroxysteroid Dehydrogenases (drug effects, genetics, metabolism)
• Medroxyprogesterone Acetate (pharmacology)
• Mifepristone (pharmacology)
• NAD (metabolism)
• Progesterone Congeners (pharmacology)
• Progestins (pharmacology)
• RNA, Messenger (drug effects)
• Tumor Cells, Cultured