Gonadotropin-Releasing Hormone (GnRH) agonist triptorelin inhibits estradiol-induced Serum Response Element (SRE) activation and c-fos expression in human endometrial, ovarian and breast cancer cells

17β-Estradiol (E2) induces c-fosprotooncogene expression in MCF-7 human breast cancer cells, and deletion analysis of the c-fospromoter showed that the serum response element (SRE) at −325 to −296 was E2-responsive. The mechanism of ligand-activated estrogen receptor α (ERα)-dependent activation of gene expression through the SRE was determined by mutational analysis of the promoter, analysis of mitogen-activated protein kinase (MAPK) pathway activation by E2, and transforming growth factor α (TGF-α) as a positive control. In addition, ERα-negative MDA-MB-231 breast cancer and Chinese hamster ovary cells were used as reference cell lines. The results showed that transcriptional activation of the SRE by E2 was due to ERα activation of the MAPK pathway and increased binding of the serum response factor and Elk-1 to the SRE. Subsequent studies with dominant negative Elk-1, wild type, and variant GAL4-Elk-1 fusion proteins confirmed that phosphorylation of Elk-1 at serines 383 and 389 in the C-terminal region of Elk-1 is an important downstream target associated with activation of an SRE by E2. Both E2 (ERα-dependent) and growth factors (ERα-independent) activated the SRE in breast cancer cells via the Ras/MAPK pathway; however, in ER-negative CHO cells that do not express a receptor for TGF-α, only hormone-induced activation was observed in cells transfected with ERα.

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Gonadotropin-releasing hormone (GnRH) agonist triptorelin inhibits estradiol-induced serum response element (SRE) activation and c-fos expression in human endometrial, ovarian and breast cancer cells

Acta Endocrinologica ◽

10.1530/eje.0.1510619 ◽

2004 ◽

pp. 619-628 ◽

Cited By ~ 22

Author(s):

C Grundker ◽

AR Gunthert ◽

M Hellriegel ◽

G Emons

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cell Lines ◽

Cancer Cell ◽

Gnrh Agonist ◽

Cancer Cell Proliferation ◽

Response Element ◽

Fos Expression ◽

Er Alpha ◽

Serum Response

BACKGROUND AND METHODS: The majority of human endometrial (>80%), ovarian (>80%) and breast (>50%) cancers express GnRH receptors. Their spontaneous and epidermal growth-factor-induced proliferation is dose- and time-dependently reduced by treatment with GnRH and its agonists. In this study, we demonstrate that the GnRH agonist triptorelin inhibits estradiol (E2)-induced cancer cell proliferation. RESULTS: The proliferation of quiescent estrogen receptor alpha (ER alpha)-/ER beta-positive, but not of ER alpha-negative/ER beta-positive endometrial, ovarian and breast cancer cell lines, was significantly stimulated (P<0.001) (ANOVA) after treatment with E2 (10(-8) M). This effect was time- and dose-dependently antagonized by simultaneous treatment with triptorelin. The inhibitory effect was maximal at 10(-5) M concentration of triptorelin (P<0.001). In addition, we could show that, in ER alpha-/ER beta-positive cell lines, E2 induces activation of serum response element (SRE) and expression of the immediate early-response gene c-fos. These effects were blocked by triptorelin (P<0.001). E2-induced activation of estrogen-response element (ERE) was not affected by triptorelin. CONCLUSIONS: The transcriptional activation of SRE by E2 is due to ER alpha activation of the mitogen-activated protein kinase (MAPK) pathway. This pathway is impeded by GnRH, resulting in a reduction of E2-induced SRE activation and, in consequence, a reduction of E2-induced c-fos expression. This causes downregulation of E2-induced cancer cell proliferation.

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