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-releas ing hormone (GnRH) via specific receptors in endometrial cancer (EC) h as 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 tis sues and cell lines to investigate the possibility of an autocrine gro wth regulation mechanism. Using reverse transcription-PCR, differing G nRH mRNA transcripts were detected in two EC cell lines (Ishikawa and HEC-1A), a choriocarcinoma (JEG3) cell line, and tissues from endometr ium and placenta, However, secretion of immunoreactive GnRH could be d etected by RIA in only 1 of 10 EC tissues in primary culture, and in n one of the cell lines, Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcriptio n-PCR and Southern blotting of the PCR product. In radioligand binding assays using GnRHa goserelin, no pituitary-like, high-affinity GnRH b inding sites could be found in either EC cell lines or tissues, Low af finity binding (K-d = 1.0-3.1 x 10(-7) M) was detected in three of eig ht (37%) EC tissues, Furthermore, receptor signal transduction measure ments carried out in these cells showed no increases in either total i nositol phosphate, cyclic AMP production, or cytosolic Ca2+ in respons e 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-f ree conditions, assessed by DNA content. Our data suggest that althoug h there is a potential for autocrine activity for GnRH in EC as judged by the presence of mRNA for peptide and receptor, no functional recep tor activity could be detected in vitro, Alternative mechanisms should be studied to explain the in vivo action of GnRHa.