Expression of the 11beta-hydroxysteroid dehydrogenase type II enzyme in breast tumors and modulation of activity and cell growth in PMC42 cells.
Manipulating the metabolism of glucocorticoids may serve as a useful adjunct in the treatment of breast cancer. The 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) potently inactivates glucocorticoids thereby protecting the non-selective mineralocorticoid receptor (MR) in fluid transporting tissues. In the present study, Western blot analysis showed the presence of 11betaHSD2 in 66% of the breast tumor samples. The 11betaHSD2 and MR are also present in the breast tumor cell line PMC42. Glycyrrhetinic acid abolished glucocorticoid metabolism and inhibited cell growth by 40%, the latter at concentrations consistent with glucocorticoid receptor (GR) and MR binding studies. Metabolism was increased by glucocorticoids, the anti-glucocorticoid RU 38486 and anti-mineralocorticoid spironolactone, while aldosterone had no effect. Neither cortisol nor aldosterone affected cell proliferation, but both RU 38486 and spironolactone caused a significant decrease in cell number. The effects of RU 38486 were only observed at micromolar concentrations and are inconsistent with an action via GR or progesterone receptor (PR). This study shows that 11betaHSD2 activity and cell proliferation of PMC42 cells can be modulated via steroid receptors.
Koyama
K
K
Laboratories of Molecular Hypertension, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Rd Central, 8008, Melbourne, Australia.
Myles
K
K
Smith
R
R
Krozowski
Z
Z
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000450:Aldosterone / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors; D018161:Receptors, Mineralocorticoid / Q000819:agonists; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D015735:Mifepristone; D000450:Aldosterone; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human