Expression of receptors for luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: Frequency, autoregulation, and correlation with direct antiproliferative activity of luteinizing hormone-releasing hormone analogues

Völker, Peter; Gründker, Carsten; Schmidt, Oswald; Schulz, K.-D.; Emons, Günter

doi:10.1067/mob.2002.119633

Cited by 119 publications

(103 citation statements)

References 14 publications

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“…In 70% of primary ovarian cancers and 83% of primary endometrial cancers, there is expression of high-affinity/low-capacity binding sites for GnRH receptors in their surfaces, and according to recent clinical data, receptor expression is a favorable prognostic factor (51, 86,87). In the majority of cases, receptor activation was related with cell-proliferation inhibition (79,86 Table I. Characteristics of GnRHR and GnRH in cancer cells.…”

Section: Gnrhr and Ovarian Cancermentioning

confidence: 99%

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

Aguilar-Rojas¹

2009

Oncol Rep

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Abstract. Human gonadotropin-releasing hormone receptor (GnRHR) and its natural ligand human gonadotropin-releasing hormone (GnRH) were initially described as signaling complexes that play a key role in reproductive functions. By binding to specific receptors present on pituitary gonadotropes, GnRH regulates the sperm and ovum maturation, as well as steroidogenesis within the context of the hypothalamushypophysis axis. The expression of GnRH and its receptor has clearly been established in many extra-pituitary organs.

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Section: Gnrhr and Ovarian Cancermentioning

confidence: 99%

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

Aguilar-Rojas¹

2009

Oncol Rep

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“…About 50% of breast, 70% of ovarian and 80% of endometrial cancers express GnRH and its receptor (Emons et al 1997, Gründker et al 2002a, Völker et al 2002 (Table 1). These findings suggested the presence of an autocrine regulatory system in these cancers based on GnRH.…”

Section: Gnrh Systems In Human Cancersmentioning

confidence: 99%

GnRH antagonists in the treatment of gynecological and breast cancers.

Emons

Gründker²,

Günthert³

et al. 2003

Endocrine-Related Cancer

133

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Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein αi and activates a variety of intracellular signaling mechanisms.(1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G 0 /G 1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.

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“…In the ovarian cancer cell line SKOV-3, which does not express GnRH-I receptors, GnRH-I agonist Triptorelin has no effects on cell proliferation (11), whereas GnRH-II has strong antiproliferative effects. It might be speculated that, in addition to the GnRH-I system, a second GnRH-system exists in human cancers.…”

Section: Introductionmentioning

confidence: 99%

GnRH-II agonist [D-Lys6]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells

Eicke

Günthert²,

Emons³

et al. 2006

Int J Oncol

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Abstract. The majority of human endometrial and ovarian cancers express receptors for GnRH type I (GnRH-I). Their proliferation is time-and dose-dependently reduced by GnRH-I and its analogs. GnRH-I analogs activate a phosphotyrosinephosphatase (PTP) and inhibit EGF-induced mitogenic signal transduction. Recently we found that GnRH type II (GnRH-II) and its agonist [D-Lys 6 ]GnRH-II also have antiproliferative effects on these tumor cells which are significantly greater than those of GnRH-I agonists. In a more recent study, we showed that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. The underlying signal transduction mechanisms of GnRH-II are still unknown. In this study we showed that the mitogenic effects of growth factors in endometrial and ovarian cancer cell lines were counteracted by GnRH-II agonist GnRH-II still activated PTP and inhibited the EGF-induced mitogenic signal transduction. These data indicate, that the effects of GnRH-II are not due to a cross-reaction with the GnRH-I receptor. In conclusion these data suggest that the signaling of GnRH-II agonist [D-Lys 6 ]GnRH-II is comparable to that of GnRH-I analogs.

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Expression of receptors for luteinizing hormone-releasing hormone in human ovarian and endometrial cancers: Frequency, autoregulation, and correlation with direct antiproliferative activity of luteinizing hormone-releasing hormone analogues

Cited by 119 publications

References 14 publications

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review)

GnRH antagonists in the treatment of gynecological and breast cancers.

GnRH-II agonist [D-Lys6]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells

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