Non-classical antiestrogenic actions of dexamethasone in variant MCF-7 human breast cancer cells in culture

doi:10.1016/0303-7207(89)90031-2

Molecular and Cellular Endocrinology

Volume 66, Issue 2, October 1989, Pages 189-197

https://doi.org/10.1016/0303-7207(89)90031-2 Get rights and content

Abstract

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 − 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 52000 and 160000 M_r 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.

References (25)

D. Chalbos et al.
Biochem. Biophys. Res.Commun.
(1984)
D. Chalbos et al.
J. Biol. Chem.
(1987)
P. Chatelain et al.
Biochem. Biophys. Res. Commun.
(1987)
C. Chouvet et al.
J. Steroid Biochem.
(1986)
C. Eil et al.
Steroids
(1980)
B.E. Linebaugh et al.
Mol. Cell. Endocrinol.
(1977)
N. Mairesse et al.
J. Steroid Biochem.
(1981)
B. Westley et al.
Biochem. Biophys. Res. Commun.
(1979)
B. Westley et al.
Cell
(1980)
E. Boisvieux-Ulrich et al.
Biol. Cell
(1984)

D. Chalbos et al.

J. Clin. Endocrinol. Metab.

(1982)

P.G. Gill et al.

Breast Cancer Res.

(1987)

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^☆: This work is supported by INSERM, Association pour la Recherche sur le Cancer and University of LYON I, Faculté de Médecine Lyon Nord and Fondation Mérieux. A large part of cell growth studies was performed by F. Zhou and the majority of biochemical studies was done by B. Bouillard. Both have to be considered as first author

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Non-classical antiestrogenic actions of dexamethasone in variant MCF-7 human breast cancer cells in culture☆

Abstract

Biochem. Biophys. Res.Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Steroid Biochem.

Steroids

Mol. Cell. Endocrinol.

J. Steroid Biochem.

Biochem. Biophys. Res. Commun.

Cell

Biol. Cell

J. Clin. Endocrinol. Metab.

Breast Cancer Res.