Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate

Borroni, Raffaella; Blasio, Anna Maria Di; Gaffuri, Barbara; Santorsola, Roberta; Busacca, Mauro; Viganò, Paola; Vignali, Mario

doi:10.1016/s0303-7207(99)00199-9

Cited by 54 publications

(42 citation statements)

References 23 publications

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“…Interestingly, similar findings were made in the Fallopian tube (40). GnRH receptors have even been detected in endometriosis: using RT-PCR and Southern blot, Borroni et al (41) were able to demonstrate the presence of these receptors in 13 of 13 samples of ovarian endometriosis; however, in cell cultures of these lesions, the GnRH agonist, leuporelin, exerted antiproliferative effects in just 5 of 13 cases. Kottler et al (42) demonstrated co-expression of GnRH and its receptor in malignant and non-malignant tissues of the human breast.…”

Section: Hypothalamic Gonadotropin-releasing Hormonementioning

confidence: 61%

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

155

139

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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.

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Section: Hypothalamic Gonadotropin-releasing Hormonementioning

confidence: 61%

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

155

139

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“…Sequence analysis reveals no mutations or alternative splicing patterns throughout the entire coding region of endometrial GnRH receptor RNA transcripts. (Borroni et al 2000, Grundker et al 2001b.…”

Section: Interaction Of Gnrh and Gnrh-r In Reproductive Tissuesmentioning

confidence: 99%

“…Because of its unique functions, analogues of GnRH have been applied for medical treatment of many hormone-related diseases such as endometriosis. Furthermore, some studies report that the GnRH system may play a role of autocrine and paracrine regulation in endometriosis since GnRH and GnRH receptor mRNA have been detected in human eutopic and ectopic endometrium (Imai et al 1994, Borroni et al 2000. Concerning the apoptosis in endometriosis induced by GnRH analogues, it was demonstrated that GnRH analogues may have a direct effect by enhancing the apoptotic index, decreasing the secretion of promitogenic cytokines such as interleukin-1b and VEGF, increasing the expression of the pro-apoptotic proteins BAX and Fas ligand, decreasing the expression of the anti-apoptotic protein BCL2 and suppressing cell proliferation in endometriosis (Meresman et al 2003, Bilotas et al 2007).…”

Section: Gnrh and Endometriosismentioning

confidence: 99%

GnRH signaling in intrauterine tissues

Wu¹,

Wang²,

Huang³

et al. 2009

Reproduction

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Type I GnRH (GnRH-I, GNRH1) and type II GnRH (GnRH-II, GNRH2), each encoded by separate genes, have been identified in humans. The tissue distribution and functional regulation of GnRH-I and GnRH-II clearly differ despite their comparable cDNA and genomic structures. These hormones exert their effects by binding to cell surface transmembrane G protein coupled receptors and stimulating the Gq/11 subfamily of G proteins. The hypothalamus and pituitary are the main origin and target sites of GnRH, but numerous studies have demonstrated that extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in different reproductive tissues such as the ovary, endometrium, placenta, and endometrial cancer cells. In addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner to suppress cell proliferation and activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms. Both GnRH-I and GnRH-II exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy. The presence of varied GnRH and GnRH receptor systems demonstrate their different roles in distinct tissues using dissimilar mechanisms. These may result in the generation of new GnRH analogues used for several hormone-related diseases.

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“…Various disease and/or transformed epithelial cells are known to express the GnRHR (Friess et al 1991, Kakar & Jennes 1995, Chatzaki et al 1996, Kottler et al 1997, Barbieri 1998, Yin et al 1998, Ortmann & Diedrich 1999, Borroni et al 2000, Halmos et al 2000, Kang et al 2000, Lee et al 2000, Noci et al 2000, and the GnRHRs present on hormonally responsive tumor cells appear to be identical to the high-affinity pituitary receptor. Recently, GnRHR-II, which transmits significantly stronger anti-proliferative effects than GnRHR-I, has been identified in ovarian and endometrial cancers (Kang et al 2000, Bedecarrats & Kaiser 2003; the significance of this remains to be determined as the role of GnRH-II has not been elucidated.…”

Section: Aberrant Expression Of Gnrhr In Cancermentioning

confidence: 99%

Gonadotropin-releasing hormone and its receptor in normal and malignant cells

Harrison

Wierman²,

Nett³

et al. 2004

Endocr Relat Cancer

153

105

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Gonadotropin-releasing hormone (GnRH) is the hypothalamic factor that mediates reproductive competence. Intermittent GnRH secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. LH and FSH then stimulate sex steroid hormone synthesis and gametogenesis in the gonads to ensure reproductive competence. The pituitary requires pulsatile stimulation by GnRH to synthesize and release the gonadotropins LH and FSH. Clinically, native GnRH is used in a pump delivery system to create an episodic delivery pattern to restore hormonal defects in patients with hypogonadotropic hypogonadism. Agonists of GnRH are delivered in a continuous mode to turn off reproductive function by inhibiting gonadotropin production, thus lowering sex steroid production, resulting in medical castration. They have been used in endocrine disorders such as precocious puberty, endometriosis and leiomyomata, but are also studied extensively in hormone-dependent malignancies. The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets. This paper reviews the current data concerning differential control of GnRH and GnRH receptor expression and signaling in the hypothalamic-pituitary axis and extrapituitary tissues. Using these data as a backdrop, we then review the literature about the action of GnRH in cancer cells, the utility of GnRH analogs in various malignancies and then update the research in novel therapies targeted to the GnRH receptor in cancer cells to promote anti-proliferative effects and control of tumor burden.

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Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate

Cited by 54 publications

References 23 publications

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Biology of the gonadotropin-releasing hormone system in gynecological cancers

GnRH signaling in intrauterine tissues

Gonadotropin-releasing hormone and its receptor in normal and malignant cells

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