Non-classical antiestrogenic actions of dexamethasone in variant MCF-7 human breast cancer cells in culture.
The aim of this work was to determine whether dexamethasone (Dex), a synthetic glucocorticoid, counteracts the stimulatory effects of estradiol (E2) on MCF-7 cells. We have shown that Dex inhibits in a dose-dependent fashion the estradiol-stimulated cell proliferation. This inhibition (ID50 congruent to 5-10 nM), which is complete at 100 nM Dex, is prevented by the antiglucocorticoid RU 486 and is clearly different from that found with trans-4-OH-tamoxifen because the inhibition due to a fixed concentration of Dex is not abolished by a high concentration of estradiol. This inhibitory effect displays some degree of specificity. Progesterone and the progestins R 5020 and ORG 2058 are without effect and Dex does not alter the triiodo-L-thyronine-stimulated cell growth. To characterize further the antiestrogenic action of Dex, the effects of this drug on specific responses to estradiol were studied. (1) Among the positive responses to estradiol two are prevented by Dex (the increase of concentration of progestin receptors and that of immunoreactive insulin-like growth factor I, IR-IGF-I, in conditioned medium) and two are insensitive to Dex (the enhancement of the secretion of 52,000 and 160,000 Mr proteins). (2) A negative response to estradiol (the down-regulation of estrogen receptor) is not prevented but rather accentuated by Dex. Thus, Dex counteracts the stimulatory effects of estradiol on the proliferation of MCF-7 cell variants characterized by progestin insensitivity. This non-classical antiestrogenic effect could be due in part to the attenuation of the E2-induced IR-IGF-I secretion and, less probably, to the accentuation of the down-regulation of E2 receptors. It could account for certain therapeutic and/or side effects of glucocorticoids on estrogen target cells.
Zhou
F
F
INSERM-U.34, Hôpital Debrousse, Lyon, France.
Bouillard
B
B
Pharaboz-Joly
M O
MO
André
J
J
D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004965:Estrogen Antagonists; D004967:Estrogens / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D011372:Progestins / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
D004965:Estrogen Antagonists; D004967:Estrogens; D005938:Glucocorticoids; D011372:Progestins; D011980:Receptors, Progesterone; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone