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.

Abstract

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.

• Authors: Carsten Gründker, Andreas R Günthert, Martin Hellriegel, Günter Emons
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 151 Issue 5 Pg. 619-28 (Nov 2004) ISSN: 0804-4643 [Print] England
• PMID: 15538941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens
• Proto-Oncogene Proteins c-fos
• Triptorelin Pamoate
• Gonadotropin-Releasing Hormone
• Estradiol

Topics

• Antineoplastic Agents, Hormonal (administration & dosage, pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Endometrial Neoplasms (metabolism, pathology)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (metabolism)
• Estrogen Receptor beta (metabolism)
• Estrogens (metabolism)
• Female
• Gene Expression (drug effects)
• Genes, fos
• Genital Neoplasms, Female (metabolism, pathology)
• Gonadotropin-Releasing Hormone (agonists)
• Humans
• Ovarian Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-fos (antagonists & inhibitors)
• Response Elements (drug effects)
• Serum Response Element (drug effects)
• Triptorelin Pamoate (administration & dosage, pharmacology)