Abstract
In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation. The expression of GnRH receptor has also been identified in breast cancers and non-reproductive cancers such as pancreatic cancers and glioblastoma. Various investigators have observed dose- and time-dependent growth inhibitory effects of GnRH agonists in cell lines derived from these cancers. GnRH antagonists have also shown marked growth inhibitory effects on most cancer cell lines. This indicates that in the GnRH system in cancer cells, there may not be a dichotomy between GnRH agonists and antagonists. The well-known signaling mechanisms of the GnRH receptor, which are present in pituitary gonadotrophs, are not involved in forwarding the antiproliferative effects of GnRH analogs in cancer cells. Instead, the GnRH receptor activates a phosphotyrosine phosphatase (PTP) and counteracts with the mitogenic signal transduction of growth factor receptors, which results in a reduction of cancer cell proliferation. The PTP activation, which is induced by GnRH, also inhibits G-protein-coupled estrogen receptor 1 (GPER), which is a membrane-bound receptor for estrogens. GPER plays an important role in breast cancers, which do not express the estrogen receptor α (ERα). In metastatic breast, ovarian, and endometrial cancer cells, GnRH reduces cell invasion in vitro, metastasis in vivo, and the increased expression of S100A4 and CYR61. All of these factors play important roles in epithelial–mesenchymal transition. This review will summarize the present state of knowledge about the GnRH receptor and its signaling in human cancers.
Highlights
In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation
We have shown that GnRH agonists cause JunD-DNA binding, which results in decreased cell proliferation shown by an increased G0/1 phase of cell cycle and reduced DNA synthesis [88]
Different studies have shown that estrogen receptor α (ERα) mediates 17β-estradiol (E2)-activated expression of c-fos, which is induced as an immediate early response gene in ERα-positive breast cancer cell lines [89,90,91,92,93,94,95,96]
Summary
Expression and sequence analysis of the GnRH receptor found in human pituitary gonadotrophs were first demonstrated in 1992 [5] Due to these findings, intensive research was carried out, which lead to the demonstration of high-affinity GnRH receptors in ovarian and endometrial cancer cell lines and in about 80% of their respective primary tumors [5,6,7,8]. High-affinity/low-capacity-binding sites, strongly related to the pituitary GnRH receptor, were found in specimens of ovarian and endometrial cancers and cell lines, which express mRNA for the GnRH receptor known from pituitary gonadotrophs [6, 7, 9,10,11,12,13]. The GnRH receptor mediates the effects of GnRH-II on prostate cancer cells [45]
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