Biology of the gonadotropin-releasing hormone system in gynecological cancers

Abstract

The expression of GnRH and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in cancer cells. Rather, the GnRH receptor interacts with the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity, via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. In addition, GnRH activates nuclear factor kB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

“…8,16 The number of patients in our study precludes speculation about association between clinical behavior and heterogeneous GnRH-R I and II expression but immunohistochemical detection of the receptors may identify tumor cells with an autocrine regulatory potential based on GnRH. 9 Interestingly, the five recurrent tumors in our series had high levels of GnRH-R I and II expression.…”

“…For immunohistochemical analysis, representative 2-mm-thick sections of the endometrial stromal sarcomas were incubated with guinea-pig antisera to GnRH-R I (1:1000) and GNRH-R II (1:2000) after proteinase pretreatment. The antisera have been preciously characterized 8,9 and were generously provided by PD Dr Gundker, Department of Obstetrics and Gynecology, Georg-August University of Goettingen, Germany. Negative staining was recorded when 0-10% of tumor cells reacted with the antibodies.…”

GPCRs and cancer

“…The activation of the peripheral GnRH receptor, which is coupled to the Gi protein in uterine leiomyosarcoma, ovarian and endometrial carcinomas, decreased intracellular cAMP levels leading to a down-regulation of gene transcription and antiproliferative effects in tumor cells [122] . Indeed, the repressive action of GnRH-I receptor on cell proliferation has been demonstrated in hormone-related tumors like prostate, breast, ovary and endometrium cancer [124] . GnRH and the cognate receptors were also involved in the stimulation of motility and invasion in ovarian cancer cells [125,126] , however several studies suggested a protective role elicited by GnRH analogues against gonadal damage during chemotherapy in diverse types of tumors [122] .…”

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The presence of GnRH receptors in breast cancer tissue [31] and the demonstration of antiproliferative actions of GnRH analogs in breast cancer cell lines [32,47,96] supported this interpretation. Antiproliferative effects of GnRH analogs and the expression of GnRH receptors have now been demonstrated in a number of cell lines of reproductive tract tumors, including prostate, uterine and ovarian cancers, and also in nonreproductive tract tumors [21,43,47,70,73,79]. In contrast to GnRH actions at the gonadotrope, which are mediated through the G αq protein, these antiproliferative and apoptotic effects on tumor cells are thought to be mediated via the G αi protein [42,54,81], focal adhesion complexes involving c-Src, and the JNK and P38 stress-activated kinases [42,54,70,73,81].…”