Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release
| Autor: | Nira Ben-Jonathan, Lauren A. Foster, Leighton Sneade, Sanjay Kansra, Sayaka Yamagata |
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| Rok vydání: | 2005 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty medicine.drug_class Estrogen receptor Biology Biochemistry Estrogen Receptor Antagonists Prolactin cell Mice Endocrinology Internal medicine Cell Line Tumor polycyclic compounds medicine Animals Estrogen Receptor beta Humans Raloxifene Molecular Biology Cell Proliferation Estrogen Antagonists Estrogen Receptor alpha Prolactin Estrogen Pituitary Gland Female hormones hormone substitutes and hormone antagonists Tamoxifen medicine.drug |
| Zdroj: | Molecular and cellular endocrinology. 239(1-2) |
| ISSN: | 0303-7207 |
| Popis: | Anti-estrogens act by inhibiting estrogen receptor (ER) function. Unlike raloxifene and tamoxifen which exhibit both antagonist and agonist properties, ICI 182,780 (ICI) is considered a "pure" anti-estrogen devoid of any agonistic activities. Whereas there is ample information on the effects of anti-estrogens on the breast and uterus, little is known about their action on the pituitary, the estrogen-sensitive master endocrine gland. Our objectives were to: (1) compare the effects of ICI, tamoxifen and raloxifene on lactotroph proliferation in the absence of estrogen, (2) determine whether their action is mediated through the ER, and (3) compare their effects on prolactin (PRL) release. We are reporting that ICI is a potent inhibitor of lactotroph proliferation (both GH3 and MMQ cells) with maximal inhibition of 45-50% seen with 1nM. ICI is several orders of magnitude more potent than raloxifene while tamoxifen has no effect. Neither anti-estrogen affects T47D breast cancer cell proliferation. GH3 cell incubation with ICI for 1h only causes maximal suppression of cell proliferation, an effect which is reversed by co-incubation with estrogen. Such a short exposure to ICI is sufficient to cause rapid and persistent downregulation of ERalpha protein, whereas downregulation of ERbeta is significantly delayed; tamoxifen and raloxifene have no appreciable effects on ER(s) levels. The ability of ICI to inhibit GH3 cell proliferation is dependent upon ERalpha, since an ERalpha, but not ERbeta, specific agonist reverses the effect of ICI. PRL release is differentially regulated by the anti-estrogens. ICI at 0.1nM suppresses PRL release from GH3 cells by 80%, with a similar strong suppression also seen with 10nM raloxifene. However, tamoxifen at 0.01nM inhibits PRL release but has no effect at 10nM. Cell co-incubation with ICI and estradiol results in a four-fold increase in PRL release. Taken together, our study shows that ICI, in the absence of exogenous estrogens, inhibits lactotroph proliferation and PRL release by downregulating or inactivating ERalpha. The dissimilar responses of cell proliferation and PRL release to the anti-estrogens suggest that both processes are regulated by different mechanisms. These data highlight the importance of studying the effects of anti-estrogens in multiple systems. |
| Databáze: | OpenAIRE |
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