Impairment of the antiproliferative effect of glucocorticosteroids by 11beta-hydroxysteroid dehydrogenase type 2 overexpression in MCF-7 breast-cancer cells.
To verify the relevance of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in controlling breast-cancer cell growth, we have evaluated the correlation of 11beta-HSD2 expression and antiproliferative effects of glucocorticosteroids (GCs) on breast cancer cell proliferation. We cloned human 11beta-HSD2 cDNA into the expression vector pBK-CMV. The interspersing lac promoter region was deleted, achieving differential translational efficiency. The constructs were stably transfected into wild-type MCF-7 breast-cancer cells possessing almost no oxidative and no reductive 11beta-HSD activity. Low (times 7) and high (times 718) 11beta-HSD2 overexpression was achieved. We compared growth behavior of transfected cells In the presence of GCs to MCF-7 cells transfected with pBK-CMV alone (internal control). The antiproliferative effects of GCs were reversed and total cell growth boosted by overexpression of 11beta-HSD2; about 50 % of the increase in cell proliferation was attained by low 11beta-HSD2 overexpression, while high enzyme overexpression led to an increase in cell growth of about 120 %. Using direct evidence, this study shows 11beta-HSD2 to impair antiproliferative glucocorticosteroid effects, thus acting as an enzymatic shield aggravating breast-cancer cell growth. These results indicate a possible therapeutic role for 11beta-HSD inhibitors in the treatment of breast cancer.
Lipka
C
C
Department of Obstetrics and Gynecology, Charité, Germany.
Mankertz
J
J
Fromm
M
M
Lübbert
H
H
Bühler
H
H
Kühn
W
W
Ragosch
V
V
Hundertmark
S
S
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2