The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

Carsten Gründker, Günter Emons, Carsten Gründker, Günter Emons

Abstract

In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation. The expression of GnRH receptor has also been identified in breast cancers and non-reproductive cancers such as pancreatic cancers and glioblastoma. Various investigators have observed dose- and time-dependent growth inhibitory effects of GnRH agonists in cell lines derived from these cancers. GnRH antagonists have also shown marked growth inhibitory effects on most cancer cell lines. This indicates that in the GnRH system in cancer cells, there may not be a dichotomy between GnRH agonists and antagonists. The well-known signaling mechanisms of the GnRH receptor, which are present in pituitary gonadotrophs, are not involved in forwarding the antiproliferative effects of GnRH analogs in cancer cells. Instead, the GnRH receptor activates a phosphotyrosine phosphatase (PTP) and counteracts with the mitogenic signal transduction of growth factor receptors, which results in a reduction of cancer cell proliferation. The PTP activation, which is induced by GnRH, also inhibits G-protein-coupled estrogen receptor 1 (GPER), which is a membrane-bound receptor for estrogens. GPER plays an important role in breast cancers, which do not express the estrogen receptor α (ERα). In metastatic breast, ovarian, and endometrial cancer cells, GnRH reduces cell invasion in vitro, metastasis in vivo, and the increased expression of S100A4 and CYR61. All of these factors play important roles in epithelial-mesenchymal transition. This review will summarize the present state of knowledge about the GnRH receptor and its signaling in human cancers.

Keywords: cancer; gonadotropin-releasing hormone; metastasis; proliferation; signal transduction.

Figures

Figure 1
Figure 1
Gonadotropin-releasing hormone (GnRH) receptor signal transduction in human cancers. Binding of GnRH or GnRH-II agonists to GnRH receptor causes G-protein αi-mediated activation of phosphotyrosine phosphatase (PTP), resulting in dephosphorylation of activated EGF receptor (EGF-R) and inhibition of EGF-R signal transduction. GnRH antagonists also show GnRH receptor-induced PTP activation. GnRH-induced activation of PTP also inhibits G-protein βγ subunit-mediated Src/MMP/HB-EGF signaling cascade of GPER and inhibits E2-induced proliferation in ERα-negative breast cancer cells. In addition, GnRH agonists activate the JNK/activator protein-1 (AP-1) pathway independent of known AP-1 activators, protein kinase C, or mitogen-activated protein kinase, resulting in an increased G0/1 phase of cell cycle and decreased DNA synthesis. GnRH-II antagonists induce apoptosis in human breast, endometrial, and ovarian cancer cells through activation of the intrinsic apoptotic pathway.
Figure 2
Figure 2
Gonadotropin-releasing hormone (GnRH) receptor-targeted chemotherapy using Zoptarelin Doxorubicin. Internalization of cytotoxic GnRH analog Zoptarelin Doxorubicin induces multidrug resistance gene (MDR-1)-independent apoptosis. After receptor binding, the Zoptarelin Doxorubicin/GnRH receptor complex is internalized via coated vesicles bypassing the MDR-1 system. Thereafter, Zoptarelin Doxorubicin is split and free doxorubicin is accumulated within the nucleus, inducing apoptosis. Detection of Zoptarelin Doxorubicin and doxorubicin was performed using laser scanning microscopy (102).

References

    1. Grundker C, Gunthert AR, Westphalen S, Emons G. Biology of the gonadotropin-releasing hormone system in gynecological cancers. Eur J Endocrinol (2002) 146:1–14.10.1530/eje.0.1460001
    1. Emons G, Schally AV. The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers. Hum Reprod (1994) 9:1364–79.10.1093/oxfordjournals.humrep.a138714
    1. Loop SM, Gorder CA, Lewis SM, Saiers JH, Drivdahl RH, Ostenson RC. Growth inhibition of human prostate tumor cells by an agonist of gonadotrophin-releasing hormone. Prostate (1995) 26:179–88.10.1002/pros.2990260403
    1. Eidne KA, Flanagan CA, Harris NS, Millar RP. Gonadotropin-releasing hormone (GnRH)-binding sites in human breast cancer cell lines and inhibitory effects of GnRH antagonists. J Clin Endocrinol Metab (1987) 64:425–32.10.1210/jcem-64-3-425
    1. Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD. Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem Biophys Res Commun (1992) 189:289–95.10.1016/0006-291X(92)91556-6
    1. Imai A, Ohno T, Iida K, Fuseya T, Furui T, Tamaya T. Gonadotropin-releasing hormone receptor in gynecologic tumors. Frequent expression in adenocarcinoma histologic types. Cancer (1994) 74:2555–61.10.1002/1097-0142(19941101)74:9<2555::AID-CNCR2820740925>;2-X
    1. Imai A, Ohno T, Iida K, Fuseya T, Furui T, Tamaya T. Presence of gonadotropin-releasing hormone receptor and its messenger ribonucleic acid in endometrial carcinoma and endometrium. Gynecol Oncol (1994) 55:144–8.10.1006/gyno.1994.1264
    1. Imai A, Ohno T, Ohsuye K, Tamaya T. Expression of gonadotropin-releasing hormone receptor in human epithelial ovarian carcinoma. Ann Clin Biochem (1994) 31(Pt 6):550–5.10.1177/000456329403100111
    1. Irmer G, Burger C, Muller R, Ortmann O, Peter U, Kakar SS, et al. Expression of the messenger RNAs for luteinizing hormone-releasing hormone (LHRH) and its receptor in human ovarian epithelial carcinoma. Cancer Res (1995) 55:817–22.
    1. Emons G, Ortmann O, Becker M, Irmer G, Springer B, Laun R, et al. High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res (1993) 53:5439–46.
    1. Emons G, Schroder B, Ortmann O, Westphalen S, Schulz KD, Schally AV. High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines. J Clin Endocrinol Metab (1993) 77:1458–64.10.1210/jc.77.6.1458
    1. Ohno T, Imai A, Furui T, Takahashi K, Tamaya T. Presence of gonadotropin-releasing hormone and its messenger ribonucleic acid in human ovarian epithelial carcinoma. Am J Obstet Gynecol (1993) 169:605–10.10.1016/0002-9378(93)90630-2
    1. Irmer G, Burger C, Ortmann O, Schulz KD, Emons G. Expression of luteinizing hormone releasing hormone and its mRNA in human endometrial cancer cell lines. J Clin Endocrinol Metab (1994) 79:916–9.10.1210/jc.79.3.916
    1. Kakar SS, Grizzle WE, Neill JD. The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary. Mol Cell Endocrinol (1994) 106:145–9.10.1016/0303-7207(94)90196-1
    1. Harris N, Dutlow C, Eidne K, Dong KW, Roberts J, Millar R. Gonadotropin-releasing hormone gene expression in MDA-MB-231 and ZR-75-1 breast carcinoma cell lines. Cancer Res (1991) 51:2577–81.
    1. Fekete M, Wittliff JL, Schally AV. Characteristics and distribution of receptors for [D-TRP6]-luteinizing hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer. J Clin Lab Anal (1989) 3:137–47.10.1002/jcla.1860030302
    1. Baumann KH, Kiesel L, Kaufmann M, Bastert G, Runnebaum B. Characterization of binding sites for a GnRH-agonist (buserelin) in human breast cancer biopsies and their distribution in relation to tumor parameters. Breast Cancer Res Treat (1993) 25:37–46.10.1007/BF00662399
    1. Moriya T, Suzuki T, Pilichowska M, Ariga N, Kimura N, Ouchi N, et al. Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma. Pathol Int (2001) 51:333–7.10.1046/j.1440-1827.2001.01210.x
    1. Mangia A, Tommasi S, Reshkin SJ, Simone G, Stea B, Schittulli F, et al. Gonadotropin releasing hormone receptor expression in primary breast cancer: comparison of immunohistochemical, radioligand and Western blot analyses. Oncol Rep (2002) 9:1127–32.10.3892/or.9.5.1127
    1. Grundker C, Bauerschmitz G, Schubert A, Emons G. Invasion and increased expression of S100A4 and CYR61 in mesenchymal transformed breast cancer cells is downregulated by GnRH. Int J Oncol (2016) 48(6):2713–21.10.3892/ijo.2016.3491
    1. Fost C, Duwe F, Hellriegel M, Schweyer S, Emons G, Grundker C. Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. Oncol Rep (2011) 25(5):1481–7.10.3892/or.2011.1188
    1. Buchholz S, Seitz S, Schally AV, Engel JB, Rick FG, Szalontay L, et al. Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist cetrorelix with growth inhibition. Int J Oncol (2009) 35:789–96.10.3892/ijo_00000391
    1. Dondi D, Limonta P, Moretti RM, Marelli MM, Garattini E, Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory LHRH loop. Cancer Res (1994) 54:4091–5.
    1. Limonta P, Dondi D, Moretti RM, Maggi R, Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J Clin Endocrinol Metab (1992) 75:207–12.10.1210/jcem.75.1.1320049
    1. Limonta P, Moretti RM, Dondi D, Marelli MM, Motta M. Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH. J Steroid Biochem Mol Biol (1994) 49:347–50.10.1016/0960-0760(94)90278-X
    1. Szepeshazi K, Schally AV, Keller G, Block NL, Benten D, Halmos G, et al. Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 [AEZS-108]. Oncotarget (2012) 3:686–99.10.18632/oncotarget.546
    1. Fekete M, Zalatnai A, Comaru-Schally AM, Schally AV. Membrane receptors for peptides in experimental and human pancreatic cancers. Pancreas (1989) 4:521–8.10.1097/00006676-198910000-00001
    1. Grundker C, Ernst J, Reutter MD, Ghadimi BM, Emons G. Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers. Oncol Rep (2011) 26:629–35.10.3892/or.2011.1340
    1. Montagnani Marelli M, Moretti RM, Mai S, Muller O, Van Groeninghen JC, Limonta P. Novel insights into GnRH receptor activity: role in the control of human glioblastoma cell proliferation. Oncol Rep (2009) 21:1277–82.10.3892/or_00000351
    1. Millar R, Lowe S, Conklin D, Pawson A, Maudsley S, Troskie B, et al. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci U S A (2001) 98:9636–41.10.1073/pnas.141048498
    1. Neill JD, Duck LW, Sellers JC, Musgrove LC. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun (2001) 282:1012–8.10.1006/bbrc.2001.4678
    1. Neill JD, Musgrove LC, Duck LW. Newly recognized GnRH receptors: function and relative role. Trends Endocrinol Metab (2004) 15:383–92.10.1016/S1043-2760(04)00186-9
    1. Stewart AJ, Katz AA, Millar RP, Morgan K. Retention and silencing of prepro-GnRH-II and type II GnRH receptor genes in mammals. Neuroendocrinology (2009) 90:416–32.10.1159/000233303
    1. Grundker C, Fost C, Fister S, Nolte N, Gunthert AR, Emons G. Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo. Breast Cancer Res (2010) 12:R49.10.1186/bcr2606
    1. Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotropin-releasing hormone II (GnRH-II) receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. J Clin Endocrinol Metab (2002) 87:1427–30.10.1210/jcem.87.3.8437
    1. Millar RP. GnRH II and type II GnRH receptors. Trends Endocrinol Metab (2003) 14:35–43.10.1016/S1043-2760(02)00016-4
    1. Millar R, Conklin D, Lofton-Day C, Hutchinson E, Troskie B, Illing N, et al. A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript. J Endocrinol (1999) 162:117–26.10.1677/joe.0.1620117
    1. Ling K, Wang P, Zhao J, Wu YL, Cheng ZJ, Wu GX, et al. Five-transmembrane domains appear sufficient for a G protein-coupled receptor: functional five-transmembrane domain chemokine receptors. Proc Natl Acad Sci U S A (1999) 96:7922–7.10.1073/pnas.96.14.7922
    1. Morgan K, Conklin D, Pawson AJ, Sellar R, Ott TR, Millar RP. A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the antisense orientation on chromosome 1q.12. Endocrinology (2003) 144:423–36.10.1210/en.2002-220622
    1. van Biljon W, Wykes S, Scherer S, Krawetz SA, Hapgood J. Type II gonadotropin-releasing hormone receptor transcripts in human sperm. Biol Reprod (2002) 67:1741–9.10.1095/biolreprod.101.002808
    1. Eicke N, Gunthert AR, Viereck V, Siebold D, Behe M, Becker T, et al. GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs. Eur J Endocrinol (2005) 153:605–12.10.1530/eje.1.02005
    1. Grundker C, Schlotawa L, Viereck V, Eicke N, Horst A, Kairies B, et al. Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor. Eur J Endocrinol (2004) 151:141–9.10.1530/eje.0.1510141
    1. Kim KY, Choi KC, Auersperg N, Leung PC. Mechanism of gonadotropin-releasing hormone (GnRH)-I and -II-induced cell growth inhibition in ovarian cancer cells: role of the GnRH-I receptor and protein kinase C pathway. Endocr Relat Cancer (2006) 13:211–20.10.1677/erc.1.01033
    1. Fister S, Gunthert AR, Aicher B, Paulini KW, Emons G, Grundker C. GnRH-II antagonists induce apoptosis in human endometrial, ovarian, and breast cancer cells via activation of stress-induced MAPKs p38 and JNK and proapoptotic protein Bax. Cancer Res (2009) 69:6473–81.10.1158/0008-5472.CAN-08-4657
    1. Montagnani Marelli M, Moretti RM, Mai S, Januszkiewicz-Caulier J, Motta M, Limonta P. Type I gonadotropin-releasing hormone receptor mediates the antiproliferative effects of GnRH-II on prostate cancer cells. J Clin Endocrinol Metab (2009) 94:1761–7.10.1210/jc.2008-1741
    1. Emons G, Grundker C, Gunthert AR, Westphalen S, Kavanagh J, Verschraegen C. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr Relat Cancer (2003) 10:291–9.10.1677/erc.0.0100291
    1. Grundker C, Volker P, Emons G. Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. Endocrinology (2001) 142:2369–80.10.1210/endo.142.6.8190
    1. Limonta P, Moretti RM, Marelli MM, Dondi D, Parenti M, Motta M. The luteinizing hormone-releasing hormone receptor in human prostate cancer cells: messenger ribonucleic acid expression, molecular size, and signal transduction pathway. Endocrinology (1999) 140:5250–6.10.1210/endo.140.11.7087
    1. Dobkin-Bekman M, Naidich M, Pawson AJ, Millar RP, Seger R, Naor Z. Activation of mitogen-activated protein kinase (MAPK) by GnRH is cell-context dependent. Mol Cell Endocrinol (2006) 252:184–90.10.1016/j.mce.2006.03.035
    1. Emons G, Muller V, Ortmann O, Schulz KD. Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. J Steroid Biochem Mol Biol (1998) 65:199–206.10.1016/S0960-0760(97)00189-1
    1. Grundker C, Volker P, Schulz KD, Emons G. Luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix inhibit EGF-induced c-fos expression in human gynecological cancers. Gynecol Oncol (2000) 78:194–202.10.1006/gyno.2000.5863
    1. Fister S, Gunthert AR, Emons G, Grundker C. Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo. Cancer Res (2007) 67:1750–6.10.1158/0008-5472.CAN-06-3222
    1. Kwon JY, Park KH, Park YN, Cho NH. Effect of cetrorelix acetate on apoptosis and apoptosis regulatory factors in cultured uterine leiomyoma cells. Fertil Steril (2005) 84:1526–8.10.1016/j.fertnstert.2005.06.022
    1. von Alten J, Fister S, Schulz H, Viereck V, Frosch KH, Emons G, et al. GnRH analogs reduce invasiveness of human breast cancer cells. Breast Cancer Res Treat (2006) 100:13–21.10.1007/s10549-006-9222-z
    1. Ziegler E, Hansen MT, Haase M, Emons G, Grundker C. Generation of MCF-7 cells with aggressive metastatic potential in vitro and in vivo. Breast Cancer Res Treat (2014) 148:269–77.10.1007/s10549-014-3159-4
    1. Olbrich T, Ziegler E, Turk G, Schubert A, Emons G, Grundker C. Kisspeptin-10 inhibits bone-directed migration of GPR54-positive breast cancer cells: evidence for a dose-window effect. Gynecol Oncol (2010) 119:571–8.10.1016/j.ygyno.2010.08.018
    1. Magliocco A, Egan C. Breast cancer metastasis: advances trough the use of in vitro co-culture model systems. In: Gunduz M, Gunduz E, editors. Breast Cancer – Focusing Tumor Micriinvironment, Stem Cells and Metastasis. Rijeka, Croatia: InTech; (2011) 511–30.
    1. Dondi D, Festuccia C, Piccolella M, Bologna M, Motta M. GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system. Oncol Rep (2006) 15:393–400.10.3892/or.15.2.393
    1. Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G. Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol (2006) 37:1217–26.10.1016/j.humpath.2006.04.015
    1. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res (2004) 10:5367–74.10.1158/1078-0432.CCR-04-0220
    1. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer (2007) 109:1721–8.10.1002/cncr.22618
    1. Lacroix M. Significance, detection and markers of disseminated breast cancer cells. Endocr Relat Cancer (2006) 13:1033–67.10.1677/ERC-06-0001
    1. Schubert A, Hawighorst T, Emons G, Grundker C. Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo. Breast Cancer Res Treat (2011) 130:783–90.10.1007/s10549-011-1358-9
    1. Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res (2005) 65:3772–80.10.1158/0008-5472.CAN-04-4510
    1. Kireeva ML, Mo FE, Yang GP, Lau LF. Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion. Mol Cell Biol (1996) 16:1326–34.10.1128/MCB.16.4.1326
    1. Mazzucchelli L. Protein S100A4: too long overlooked by pathologists? Am J Pathol (2002) 160:7–13.10.1016/S0002-9440(10)64342-8
    1. Mahon PC, Baril P, Bhakta V, Chelala C, Caulee K, Harada T, et al. S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. Cancer Res (2007) 67:6786–95.10.1158/0008-5472.CAN-07-0440
    1. Leask A, Abraham DJ. All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci (2006) 119:4803–10.10.1242/jcs.03270
    1. Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE. Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endocr Relat Cancer (2004) 11:781–91.10.1677/erc.1.00825
    1. Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP. Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Res (2001) 61:8917–23.
    1. Jenkinson SR, Barraclough R, West CR, Rudland PS. S100A4 regulates cell motility and invasion in an in vitro model for breast cancer J Cancer (2004) 90:253–62.10.1038/sj.bjc.6601483
    1. Lin J, Huo R, Wang L, Zhou Z, Sun Y, Shen B, et al. A novel anti-Cyr61 antibody inhibits breast cancer growth and metastasis in vivo. Cancer Immunol Immunother (2012) 61:677–87.10.1007/s00262-011-1135-y
    1. Lee MT, Liebow C, Kamer AR, Schally AV. Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation and dephosphorylation of tyrosine residues of specific protein substrates in various tumors. Proc Natl Acad Sci U S A (1991) 88:1656–60.10.1073/pnas.88.5.1656
    1. Furui T, Imai A, Takagi H, Horibe S, Fuseya T, Tamaya T. Phosphotyrosine phosphatase-activity in membranes from endometrial carcinoma. Oncol Rep (1995) 2:1055–7.
    1. Imai A, Takagi H, Horibe S, Fuseya T, Tamaya T. Coupling of gonadotropin-releasing hormone receptor to Gi protein in human reproductive tract tumors. J Clin Endocrinol Metab (1996) 81:3249–53.10.1210/jc.81.9.3249
    1. Imai A, Takagi H, Furui T, Horibe S, Fuseya T, Tamaya T. Evidence for coupling of phosphotyrosine phosphatase to gonadotropin-releasing hormone receptor in ovarian carcinoma membrane. Cancer (1996) 77:132–7.10.1002/(SICI)1097-0142(19960101)77:1<132::AID-CNCR22>;2-5
    1. Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM. Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature (1985) 313:231–3.10.1038/313231a0
    1. Yano T, Pinski J, Halmos G, Szepeshazi K, Groot K, Schally AV. Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75. Proc Natl Acad Sci U S A (1994) 91:7090–4.10.1073/pnas.91.15.7090
    1. Moretti RM, Marelli MM, Dondi D, Poletti A, Martini L, Motta M, et al. Luteinizing hormone-releasing hormone agonists interfere with the stimulatory actions of epidermal growth factor in human prostatic cancer cell lines, LNCaP and DU 145. J Clin Endocrinol Metab (1996) 81:3930–7.10.1210/jc.81.11.3930
    1. Shirahige Y, Cook C, Pinski J, Halmos G, Nair R, Schally A. Treatment with luteinizing-hormone-releasing hormone antagonist sb-75 decreases levels of epidermal growth-factor receptor and its messenger-RNA in ov-1063 human epithelial ovarian-cancer xenografts in nude-mice. Int J Oncol (1994) 5:1031–5.
    1. Keri G, Balogh A, Szoke B, Teplan I, Csuka O. Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell line. Tumour Biol (1991) 12:61–7.10.1159/000217689
    1. Liebow C, Lee MT, Kamer AR, Schally AV. Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous and autologous receptor-stimulated tyrosine phosphorylation. Proc Natl Acad Sci U S A (1991) 88:2244–8.10.1073/pnas.88.6.2244
    1. Hershkovitz E, Marbach M, Bosin E, Levy J, Roberts CT, Jr, LeRoith D, et al. Luteinizing hormone-releasing hormone antagonists interfere with autocrine and paracrine growth stimulation of MCF-7 mammary cancer cells by insulin-like growth factors. J Clin Endocrinol Metab (1993) 77:963–8.10.1210/jc.77.4.963
    1. Grundker C, Schlotawa L, Viereck V, Emons G. Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin. Eur J Endocrinol (2001) 145:651–8.10.1530/eje.0.1450651
    1. Yamauchi J, Itoh H, Shinoura H, Miyamoto Y, Hirasawa A, Kaziro Y, et al. Involvement of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase in alpha1B-adrenergic receptor/Galphaq-induced inhibition of cell proliferation. Biochem Biophys Res Commun (2001) 281:1019–23.10.1006/bbrc.2001.4472
    1. Bigsby RM, Li A. Differentially regulated immediate early genes in the rat uterus. Endocrinology (1994) 134:1820–6.10.1210/endo.134.4.8137748
    1. Seppanen M, Lin L, Punnonen J, Grenman S, Punnonen R, Vihko KK. Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB. Eur J Endocrinol (2000) 142:393–401.10.1530/eje.0.1420393
    1. Gunthert AR, Grundker C, Hollmann K, Emons G. Luteinizing hormone-releasing hormone induces JunD-DNA binding and extends cell cycle in human ovarian cancer cells. Biochem Biophys Res Commun (2002) 294:11–5.10.1016/S0006-291X(02)00427-8
    1. Bonapace IM, Addeo R, Altucci L, Cicatiello L, Bifulco M, Laezza C, et al. 17 beta-estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation. Oncogene (1996) 12:753–63.
    1. Doucas V, Spyrou G, Yaniv M. Unregulated expression of c-Jun or c-Fos proteins but not Jun D inhibits oestrogen receptor activity in human breast cancer derived cells. EMBO J (1991) 10:2237–45.
    1. Duan R, Porter W, Safe S. Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology (1998) 139:1981–90.10.1210/endo.139.4.5870
    1. van der Burg B, de Groot RP, Isbrucker L, Kruijer W, de Laat SW. Stimulation of TPA-responsive element activity by a cooperative action of insulin and estrogen in human breast cancer cells. Mol Endocrinol (1990) 4:1720–6.10.1210/mend-4-11-1720
    1. van der Burg B, de Groot RP, Isbrucker L, Kruijer W, de Laat SW. Oestrogen directly stimulates growth factor signal transduction pathways in human breast cancer cells. J Steroid Biochem Mol Biol (1991) 40:215–21.10.1016/0960-0760(91)90185-8
    1. van der Burg B, van Selm-Miltenburg AJ, de Laat SW, van Zoelen EJ. Direct effects of estrogen on c-fos and c-myc protooncogene expression and cellular proliferation in human breast cancer cells. Mol Cell Endocrinol (1989) 64:223–8.10.1016/0303-7207(89)90149-4
    1. Weisz A, Bresciani F. Estrogen regulation of proto-oncogenes coding for nuclear proteins. Crit Rev Oncog (1993) 4:361–88.
    1. Wilding G, Lippman ME, Gelmann EP. Effects of steroid hormones and peptide growth factors on protooncogene c-fos expression in human breast cancer cells. Cancer Res (1988) 48:802–5.
    1. Duan R, Xie W, Burghardt RC, Safe S. Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1. J Biol Chem (2001) 276:11590–8.10.1074/jbc.M005492200
    1. Duan R, Xie W, Li X, McDougal A, Safe S. Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells. Biochem Biophys Res Commun (2002) 294:384–94.10.1016/S0006-291X(02)00499-0
    1. Grundker C, Gunthert AR, Hellriegel M, Emons G. Gonadotropin-releasing hormone (GnRH) agonist triptorelin inhibits estradiol-induced serum response element (SRE) activation and c-fos expression in human endometrial, ovarian and breast cancer cells. Eur J Endocrinol (2004) 151:619–28.10.1530/eje.0.1510619
    1. Girgert R, Emons G, Grundker C. Inactivation of GPR30 reduces growth of triple-negative breast cancer cells: possible application in targeted therapy. Breast Cancer Res Treat (2012) 134:199–205.10.1007/s10549-012-1968-x
    1. Girgert R, Emons G, Grundker C. Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17beta-estradiol. BMC Cancer (2014) 14:935.10.1186/1471-2407-14-935
    1. Girgert R, Emons G, Grundker C. 17beta-estradiol-induced growth of triple-negative breast cancer cells is prevented by the reduction of GPER expression after treatment with gefitinib. Oncol Rep (2017) 37:1212–8.10.3892/or.2016.5306
    1. Luttrell LM, Daaka Y, Lefkowitz RJ. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr Opin Cell Biol (1999) 11:177–83.10.1016/S0955-0674(99)80023-4
    1. Gunthert AR, Grundker C, Olota A, Lasche J, Eicke N, Emons G. Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen. Eur J Endocrinol (2005) 153:613–25.10.1530/eje.1.01996
    1. Grundker C, Volker P, Griesinger F, Ramaswamy A, Nagy A, Schally AV, et al. Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. Am J Obstet Gynecol (2002) 187:528–37.10.1067/mob.2002.124278
    1. Schally AV, Nagy A. Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur J Endocrinol (1999) 141:1–14.10.1530/eje.0.1410001
    1. Westphalen S, Kotulla G, Kaiser F, Krauss W, Werning G, Elsasser HP, et al. Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines. Int J Oncol (2000) 17:1063–72.10.3892/ijo.17.5.1063
    1. Engel JB, Schally AV, Dietl J, Rieger L, Honig A. Targeted therapy of breast and gynecological cancers with cytotoxic analogues of peptide hormones. Mol Pharm (2007) 4:652–8.10.1021/mp0700514
    1. Gunthert AR, Grundker C, Bongertz T, Nagy A, Schally AV, Emons G. Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multidrug resistance-1 (MDR-1) system. Breast Cancer Res Treat (2004) 87:255–64.10.1007/s10549-004-8806-8
    1. Gunthert AR, Grundker C, Bongertz T, Schlott T, Nagy A, Schally AV, et al. Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system. Am J Obstet Gynecol (2004) 191:1164–72.10.1016/j.ajog.2004.04.020
    1. Emons G, Kaufmann M, Gorchev G, Tsekova V, Grundker C, Gunthert AR, et al. Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. Gynecol Oncol (2010) 119:457–61.10.1016/j.ygyno.2010.08.003
    1. Emons G, Gorchev G, Harter P, Wimberger P, Stahle A, Hanker L, et al. Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5). Int J Gynecol Cancer (2014) 24:260–5.10.1097/IGC.0000000000000044
    1. Emons G, Gorchev G, Sehouli J, Wimberger P, Stahle A, Hanker L, et al. Efficacy and safety of AEZS-108 (INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the ago-study group (AGO GYN 5). Gynecol Oncol (2014) 133:427–32.10.1016/j.ygyno.2014.03.576

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe