The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor

The presence of a direct extra-pituitary action of gonadotropin-releasing hormone (GnRH) via specific receptors in endometrial cancer (EC) has been suggested as an explanation for the therapeutic effect of GnRH analogue (GnRHa) in recurrent disease. We have sought the expression of the GnRH peptide...

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Published in:Cancer research (Chicago, Ill.) Ill.), 1996-05, Vol.56 (9), p.2059-2065
Main Authors: CHATZAKI, E, BAX, C. M. R, EIDNE, K. A, ANDERSON, L, GRUDZINSKAS, J. G, GALLAGHER, C. J
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological and medical sciences
Calcium - metabolism
Endometrial Neoplasms - metabolism
Female
Female genital diseases
Gonadotropin-Releasing Hormone - biosynthesis
Gynecology. Andrology. Obstetrics
Humans
Ligands
Medical sciences
Mice
Molecular Sequence Data
Polymerase Chain Reaction
Radioligand Assay
Receptors, LHRH - biosynthesis
RNA, Messenger - biosynthesis
Tumor Cells, Cultured
Tumors
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Summary:The presence of a direct extra-pituitary action of gonadotropin-releasing hormone (GnRH) via specific receptors in endometrial cancer (EC) has been suggested as an explanation for the therapeutic effect of GnRH analogue (GnRHa) in recurrent disease. We have sought the expression of the GnRH peptide and functional GnRH receptor (GnRH-R) in human tissues and cell lines to investigate the possibility of an autocrine growth regulation mechanism. Using reverse transcription-PCR, differing GnRH mRNA transcripts were detected in two EC cell lines (Ishikawa and HEC-1A), a choriocarcinoma (JEG3) cell line, and tissues from endometrium and placenta. However, secretion of immunoreactive GnRH could be detected by RIA in only 1 of 10 EC tissues in primary culture, and in none of the cell lines. Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcription-PCR and Southern blotting of the PCR product. In radioligand binding assays using GnRHa goserelin, no pituitary-like, high-affinity GnRH binding sites could be found in either EC cell lines or tissues. Low affinity binding (Kd = 1.0 - 3.1 x 10(-7)M) was detected in three of eight (37%) EC tissues. Furthermore, receptor signal transduction measurements carried out in these cells showed no increases in either total inositol phosphate, cyclic AMP production, or cytosolic Ca2+ in response to either GnRH or GnRHa. Finally, no effect of either GnRH or GnRHa on the growth of EC cell lines was detected in vitro, under estrogen-free conditions, assessed by DNA content. Our data suggest that although there is a potential for autocrine activity for GnRH in EC as judged by the presence of mRNA for peptide and receptor, no functional receptor activity could be detected in vitro. Alternative mechanisms should be studied to explain the in vitro action of GnRHa.
ISSN:0008-5472
1538-7445