Biology of GnRH Systems in Breast and Gynaecological Cancers
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Group Leaders: Prof. Dr. rer. nat. Carsten Gründker and Prof. Dr. med. Günter Emons

The expression of GnRH-I 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-I agonists in cell lines derived from these cancers have been observed by various investigators. GnRH-I 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-I system in cancer cells. The classical GnRH-I receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH-I analogs in cancer cells. The GnRH-I receptor rather 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-I activates nucleus factor kB (NFkB) and protects the cancer cells from apoptosis. Furthermore GnRH-I induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Moreover, GnRH-I induces JunD-DNA binding and extends cell cycle. We propose that JunD activated by GnRH-I acts as a modulator of cell proliferation and cooperates with the anti-apoptotic functions of GnRH-I.
Recently we could show that GnRH type II (GnRH-II) has antiproliferative effects on these tumor cells which are significantly greater than those of the superactive GnRH-I agonist Triptorelin. In the ovarian cancer cell line SK-OV-3 which does not express GnRH-I receptors, GnRH-I agonist Triptorelin had no effects on cell proliferation whereas GnRH-I antagonist Cetrorelix and GnRH-II agonist [D-Lys6]GnRH-II had strong antiproliferative effects. These findings suggest that the antiproliferative effects of GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys6]GnRH-II are not due to a cross reaction with the GnRH-I receptor. It might be speculated that in addition to the autocrine GnRH-I system an additional autocrine system based on GnRH exists in human cancers. However, until now, attempts to clone and sequence of a full-length human GnRH-II receptor have not been successful. Morgan et al. (2003) found that the human GnRH-II receptor is expressed as a variety of splice variants and a functional human GnRH-II receptor transcript was not found. The GnRH-II receptor-like mRNA detected in previous study (Gründker et al. 2002) is suspected to be unfunctional because of the stop codon in this sequence. Thus, further investigations are required to identify the receptor that mediated the activities of GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys6]GnRH-II and elucidate the whole mechanisms of these effects.
We have assessed whether or not the antiproliferative effects of GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys6]GnRH-II in endometrial and ovarian cancer cells are mediated through the GnRH-I receptor. For this purpose we analyzed the antiproliferative effects of GnRH-I agonist Triptorelin, GnRH-I antagonist Cetrorelix and of GnRH-II in a panel of endometrial and ovarian cancer cell lines expressing GnRH-I receptors and in SK-OV-3 ovarian cancer cell line that do not express GnRH-I receptors. In addition, we knocked down the GnRH-I receptor in 4 GnRH-I receptor positive cell lines and studied the antiproliferative effects of GnRH-I agonist Triptorelin, GnRH-I antagonist Cetrorelix and GnRH-II agonist [D-Lys6]GnRH-II . After knock down of the GnRH-I receptor the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys6]GnRH-II were still existing. These data suggest that in endometrial and ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and of GnRH-II agonist [D-Lys6]GnRH-II are not mediated through the GnRH-I receptor.

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