Gonadotropin-Releasing Hormone Binding Sites in Human Breast Carcinoma

Eidne, Karin A.; Flanagan, Colleen A.; Millar, Robert P.

doi:10.1126/science.2992093

Cited by 166 publications

(87 citation statements)

References 22 publications

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“…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].…”

Section: Direct Inhibition Of Proliferation and Stimulation Of Apoptomentioning

confidence: 77%

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

Millar

Pawson

Morgan

et al. 2008

Frontiers in Neuroendocrinology

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122

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Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G q signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.

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Section: Direct Inhibition Of Proliferation and Stimulation Of Apoptomentioning

confidence: 77%

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

Millar

Pawson

Morgan

et al. 2008

Frontiers in Neuroendocrinology

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122

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“…The specific function of GnRH I and its receptor in these extrapituitary sites is unclear. However, an autocrine/paracrine function has been suggested (11,12). Linked to this hypothesis is the well-documented observation that direct application of GnRH analogs to peripheral reproductive tumor cells results in an attenuation of cellular proliferation and activation of cell death mechanisms (refs.…”

Section: Introductionmentioning

confidence: 99%

Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a Gαi-Coupling State of the Type I GnRH Receptor

et al. 2004

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Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the G␣ i -type G protein, in contrast to the predominant G␣ q coupling in gonadotropes. Unlike G␣ q coupling, G␣ i coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type II GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a G␣ i -mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced G␣ q -based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the G␣ i -coupled form of the type I GnRH receptor.

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“…In vitro studies have suggested that this new variant may interact with the full-length GnRH receptor and impair signaling by reducing agonist-induced accumulation of inositol phosphate (17). In humans, controversial data have been obtained relating to the presence of extrapituitary GnRH-binding sites in breast (18,19), placenta (20), ovaries (21) and testis (22). Northern blot analysis failed to detect GnRHR mRNAs in any of the nonpituitary tissues examined (5).…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene

Kottler

Bergametti²,

Carre³

et al. 1999

European Journal of Endocrinology

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The expression pattern of the GnRH receptor was investigated in a variety of normal and neoplastic human tissues by RT-PCR-Southern blotting. In addition to the full-length cDNA (sb1), we identified two other transcripts: the first (sb2) was characterized by a 128 bp deletion as previously described; the second was an unexpected finding composed of a shorter cDNA (sb3), the sequence of which revealed a 220 bp deletion corresponding in size to exon 2. These three transcripts were found in normal pituitary and pituitary adenomas, and in granulosa tumors, but not in testis, where sb2 was lacking. Only sb1 was expressed in normal, fibrocystic and malignant breast tissue. No transcript with a full-length region was found in endometrium, intestine or lymphocytes. This is the first report that shows that splicing of the gonadotropin-releasing hormone receptor gene is tissue dependent.We also determined the intron-exon nucleotide sequence of the gene and identified an MaeIII polymorphic site in exon 1 created by a silent C453T transition found in 10% of unrelated French whites.

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Gonadotropin-Releasing Hormone Binding Sites in Human Breast Carcinoma

Cited by 166 publications

References 22 publications

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

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

Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a Gαi-Coupling State of the Type I GnRH Receptor

Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene

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