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.
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.
Gründker
Carsten
C
Department of Gynecology and Obstetrics, Georg-August-University, D-37099 Göttingen, Germany.
Günthert
Andreas R
AR
Hellriegel
Martin
M
Emons
Günter
G
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D005833:Genital Neoplasms, Female / Q000378:metabolism* / Q000473:pathology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors*; D020218:Response Elements / Q000187:drug effects; D027602:Serum Response Element / Q000187:drug effects*; D017329:Triptorelin Pamoate / Q000008:administration & dosage / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol