Download PDF
Exp Clin Endocrinol Diabetes 2021; 129(09): 634-643
DOI: 10.1055/a-1274-1330
Article

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

Hande Mefkure Ozkaya
1   Department of Endocrinology and Metabolism, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
,
Muge Sayitoglu
2   Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul
,
Nil Comunoglu
3   Department of Pathology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
,
Eda Sun
2   Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul
,
Fatma Ela Keskin
4   Department of Endocrinology and Metabolism, Demiroglu Bilim University, Istanbul
,
Duygu Ozata
5   Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
,
Rabia Hacer Hocaoglu
5   Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
,
Khusan Khodzaev
2   Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul
,
Sinem Firtina
2   Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul
,
Necmettin Tanriover
6   Department of Neurosurgery, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
8   Pituitary Center, Istanbul University-Cerrahpasa, Istanbul
,
Nurperi Gazioglu
7   Department of Neurosurgery, Demiroglu Bilim University, Istanbul
,
Buge Oz
3   Department of Pathology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
,
Pinar Kadioglu
1   Department of Endocrinology and Metabolism, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul
8   Pituitary Center, Istanbul University-Cerrahpasa, Istanbul
› Author Affiliations Funding: The study was supported by the Research Fund of the Istanbul University, Istanbul, Turkey, project number 46991.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Purpose To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA).

Methods Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry.

Results There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERβ gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERβ protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERβ, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04).

Conclusions GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERβ, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

Key words

acromegaly - aromatase - estrogens - hormones - GPER1 - pituitary tumor


Publication History

Received: 12 June 2020
Received: 30 August 2020

Accepted: 29 September 2020

Article published online:
22 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis 2000; 21: 427-433 DOI: 10.1093/carcin/21.3.427
    CrossrefPubMedGoogle Scholar
  • 2 Yue W, Yager JD, Wang JP. et al. Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 2013; 78: 161-170 DOI: 10.1016/j.steroids.2012.11.001.
    CrossrefPubMedGoogle Scholar
  • 3 Caglar AS, Kapucu A, Dar KA. et al. Localization of the aromatase enzyme expression in the human pituitary gland and its effect on growth hormone, prolactin, and thyroid stimulating hormone axis. Endocrine 2015; 49: 761-768 DOI: 10.1007/s12020-015-0537-6.
    CrossrefPubMedGoogle Scholar
  • 4 Ozkaya HM, Comunoglu N, Keskin FE. et al. Locally produced estrogen through aromatization might enhance tissue expression of pituitary tumor transforming gene and fibroblast growth factor 2 in growth hormone-secreting adenomas. Endocrine 2016; 52: 632-640 DOI: 10.1007/s12020-015-0802-8.
    CrossrefPubMedGoogle Scholar
  • 5 Kadioglu P, Oral G, Sayitoglu M. et al. Aromatase cytochrome P450 enzyme expression in human pituitary. Pituitary 2008; 11: 29-35 DOI: 10.1007/s11102-007-0065-3.
    CrossrefPubMedGoogle Scholar
  • 6 Akinci H, Kapucu A, Dar KA. et al. Aromatase cytochrome P450 enzyme expression in prolactinomas and its relationship to tumor behavior. Pituitary 2013; 16: 386-392 DOI: 10.1007/s11102-012-0436-2.
    CrossrefPubMedGoogle Scholar
  • 7 Selek A, Cetinarslan B, Gurbuz Y. et al. Aromatase enzyme expression in acromegaly and its possible relationship with disease prognosis. Endocrine 2015; 49: 250-257 DOI: 10.1007/s12020-014-0445-1.
    CrossrefPubMedGoogle Scholar
  • 8 Simpson E, Rubin G, Clyne C. et al. Local estrogen biosynthesis in males and females. Endocrine-related cancer 1999; 6: 131-137 DOI: 10.1677/erc.0.0060131.
    CrossrefPubMedGoogle Scholar
  • 9 Leaes CG, Meurer RT, Coutinho LB. et al. Immunohistochemical expression of aromatase and estrogen, androgen and progesterone receptors in normal and neoplastic human meningeal cells. Neuropathology : Official Journal of the Japanese Society of Neuropathology 2010; 30: 44-49 DOI: 10.1111/j.1440-1789.2009.01047.x.
    CrossrefPubMedGoogle Scholar
  • 10 Singer CF, Fink-Retter A, Gschwantler-Kaulich D. et al. Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: Evidence for imbalance of local estrogen metabolism. Endocrine-related Cancer 2006; 13: 1101-1107 DOI: 10.1677/erc.1.01230.
    CrossrefPubMedGoogle Scholar
  • 11 Deblois G, Giguère V. Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer 2013; 13: 27-36 DOI: 10.1038/nrc3396
    CrossrefPubMedGoogle Scholar
  • 12 Russo J, Hasan Lareef M, Balogh G. et al. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. The Journal of Steroid Biochemistry and Molecular Biology 2003; 87: 1-25 DOI: 10.1016/S0960-0760(03)00390-X.
    CrossrefPubMedGoogle Scholar
  • 13 Filardo EJ, Thomas P. Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology 2012; 153: 2953-2962 DOI: 10.1210/en.2012-1061
    CrossrefPubMedGoogle Scholar
  • 14 Heldring N, Pike A, Andersson S. et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87: 905-931 DOI: 10.1152/physrev.00026.2006.
    CrossrefPubMedGoogle Scholar
  • 15 Heaney AP, Fernando M, Melmed S. Functional role of estrogen in pituitary tumor pathogenesis. J Clin Invest 2002; 109: 277-283 DOI: 10.1172/jci14264
    CrossrefPubMedGoogle Scholar
  • 16 Mete O, Ezzat S, Asa SL. Biomarkers of aggressive pituitary adenomas. J Mol Endocrinol 2012; 49: R69-R78 DOI: 10.1530/jme-12-0113
    CrossrefPubMedGoogle Scholar
  • 17 Friend KE, Chiou YK, Lopes MB. et al. Estrogen receptor expression in human pituitary: correlation with immunohistochemistry in normal tissue, and immunohistochemistry and morphology in macroadenomas. The Journal of Clinical Endocrinology & Metabolism 1994; 78: 1497-1504 DOI: 10.1210/jcem.78.6.7515390.
    CrossrefPubMedGoogle Scholar
  • 18 Zafar M, Ezzat S, Ramyar L. et al. Cell-specific expression of estrogen receptor in the human pituitary and its adenomas. The Journal of Clinical Endocrinology & Metabolism 1995; 80: 3621-3627 DOI: 10.1210/jcem.80.12.8530610.
    CrossrefPubMedGoogle Scholar
  • 19 Jaffrain-Rea ML, Petrangeli E, Ortolani F. et al. Cellular receptors for sex steroids in human pituitary adenomas 1996; 151: 175 DOI: 10.1677/joe.0.1510175.
    CrossrefPubMed
  • 20 Gittoes NJL, McCabe CJ, Verhaeg J. et al. Thyroid hormone and estrogen receptor expression in normal pituitary and nonfunctioning tumors of the anterior pituitary1. The Journal of Clinical Endocrinology & Metabolism 1997; 82: 1960-1967 DOI: 10.1210/jcem.82.6.3969.
    CrossrefPubMedGoogle Scholar
  • 21 Stefaneanu L. Pituitary Sex Steroid Receptors: Localization and Function. Endocr Pathol 1997; 8: 91-108 DOI: 10.1007/bf02739938
    CrossrefPubMedGoogle Scholar
  • 22 Heaney AP, Horwitz GA, Wang Z. et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nature Medicine 1999; 5: 1317-1321 DOI: 10.1038/15275.
    CrossrefPubMedGoogle Scholar
  • 23 Filardo EJ. A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis. J Steroid Biochem Mol Biol 2018; 176: 38-48 DOI: 10.1016/j.jsbmb.2017.05.005
    CrossrefPubMedGoogle Scholar
  • 24 Hazell GG, Yao ST, Roper JA. et al. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J Endocrinol 2009; 202: 223-236 DOI: 10.1677/joe-09-0066.
    CrossrefPubMedGoogle Scholar
  • 25 Camilletti MA, Abeledo-Machado A, Ferraris J. et al. Role of GPER in the anterior pituitary gland focusing on lactotroph function 2019; 240: 99 DOI: 10.1530/joe-18-0402.
    CrossrefPubMed
  • 26 Mitsui T, Ishida M, Izawa M. et al. Activation of G protein-coupled estrogen receptor 1 mimics, but does not mediate, the anti-proliferative action of estradiol on pituitary lactotrophs in primary culture. Endocrine Journal 2017; 64: 103-115 DOI: 10.1507/endocrj.EJ16-0079.
    CrossrefPubMedGoogle Scholar
  • 27 Jacenik D, Cygankiewicz AI, Krajewska WM. The G protein-coupled estrogen receptor as a modulator of neoplastic transformation. Mol Cell Endocrinol 2016; 429: 10-18 DOI: 10.1016/j.mce.2016.04.011
    CrossrefPubMedGoogle Scholar
  • 28 Pereira-Lima JF, Marroni CP, Pizarro CB. et al. Immunohistochemical detection of estrogen receptor alpha in pituitary adenomas and its correlation with cellular replication. Neuroendocrinology 2004; 79: 119-124 DOI: 10.1159/000077269.
    CrossrefPubMedGoogle Scholar
  • 29 Shupnik MA, Pitt LK, Soh AY. et al. Selective Expression of Estrogen Receptor α and β Isoforms in Human Pituitary Tumors1. The Journal of Clinical Endocrinology & Metabolism 1998; 83: 3965-3972 DOI: 10.1210/jcem.83.11.5236.
    CrossrefPubMedGoogle Scholar
  • 30 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408 DOI: 10.1006/meth.2001.1262
    CrossrefPubMedGoogle Scholar
  • 31 Hirsch FR, Varella-Garcia M, Bunn PA. et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003; 21: 3798-3807 DOI: 10.1200/jco.2003.11.069.
    CrossrefPubMedGoogle Scholar
  • 32 Pirker R, Pereira JR, von Pawel J. et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33-42 DOI: 10.1016/s1470-2045(11)70318-7.
    CrossrefPubMedGoogle Scholar
  • 33 Katznelson L, Laws ER, Melmed S. et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951 DOI: 10.1210/jc.2014-2700.
    CrossrefPubMedGoogle Scholar
  • 34 Daly AF, Beckers A. The Epidemiology of Pituitary Adenomas. Endocrinology and Metabolism Clinics of North America 2020; 49: 347-355 DOI: https://doi.org/10.1016/j.ecl.2020.04.002
    CrossrefPubMedGoogle Scholar
  • 35 Greenbaum D, Colangelo C, Williams K. et al. Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003; 4: 117 DOI: 10.1186/gb-2003-4-9-117.
    CrossrefPubMedGoogle Scholar
  • 36 Garcia-Barrado MJ, Blanco EJ, Iglesias-Osma MC. et al. Relation among Aromatase P450 and Tumoral Growth in Human Prolactinomas. Int J Mol Sci 2017; 18 DOI: 10.3390/ijms18112299.
    CrossrefPubMedGoogle Scholar
  • 37 Iruthayanathan M, Zhou YH, Childs GV. Dehydroepiandrosterone restoration of growth hormone gene expression in aging female rats, in vivo and in vitro: Evidence for actions via estrogen receptors. Endocrinology 2005; 146: 5176-5187 DOI: 10.1210/en.2005-0811
    CrossrefPubMedGoogle Scholar
  • 38 Weissberger AJ, Ho KK. Activation of the somatotropic axis by testosterone in adult males: Evidence for the role of aromatization. The Journal of Clinical Endocrinology and Metabolism 1993; 76: 1407-1412 DOI: 10.1210/jcem.76.6.8501143
    PubMedGoogle Scholar
  • 39 McCabe CJ, Khaira JS, Boelaert K. et al. Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: Relationships to clinical tumour behaviour. Clinical Endocrinology 2003; 58: 141-150 DOI: 10.1046/j.1365-2265.2003.01598.x.
    CrossrefPubMedGoogle Scholar
  • 40 Fukui S, Otani N, Nawashiro H. et al. Subcellular localization of basic fibroblast growth factor and fibroblast growth factor receptor 1 in pituitary adenomas. Brain Tumor Pathology 2002; 19: 23-29 DOI: 10.1007/bf02482452.
    CrossrefPubMedGoogle Scholar
  • 41 Suzui H, Takahashi JA, Fukumoto M. et al. Immunohistochemical study for basic fibroblast growth factor and fibroblast growth factor receptor I in pituitary adenomas. Neuroscience Letters 1994; 171: 192-196 DOI: 10.1016/0304-3940(94)90637-8.
    CrossrefPubMedGoogle Scholar
  • 42 Xiao JQ, Liu XH, Hou B. et al. Correlations of pituitary tumor transforming gene expression with human pituitary adenomas: A meta-analysis. PLoS One 2014; 9: e90396 DOI: 10.1371/journal.pone.0090396.
    CrossrefPubMedGoogle Scholar
  • 43 Ezzat S, Smyth HS, Ramyar L. et al. Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. The Journal of Clinical Endocrinology and Metabolism 1995; 80: 878-884 DOI: 10.1210/jcem.80.3.7883846.
    CrossrefPubMedGoogle Scholar
  • 44 Jia W, Lu R, Jia G. et al. Expression of pituitary tumor transforming gene (PTTG) in human pituitary macroadenomas. Tumour biology : The journal of the International Society for Oncodevelopmental Biology and Medicine 2013; 34: 1559-1567 DOI: 10.1007/s13277-013-0686-2.
    CrossrefPubMedGoogle Scholar
  • 45 Salehi F, Kovacs K, Scheithauer BW. et al. Immunohistochemical expression of pituitary tumor transforming gene (PTTG) in pituitary adenomas: A correlative study of tumor subtypes. Int J Surg Pathol 2010; 18: 5-13 DOI: 10.1177/1066896909356105.
    CrossrefPubMedGoogle Scholar
  • 46 Olde B, Leeb-Lundberg LM. GPR30/GPER1: searching for a role in estrogen physiology. Trends Endocrinol Metab 2009; 20: 409-416 DOI: 10.1016/j.tem.2009.04.006
    CrossrefPubMedGoogle Scholar
  • 47 Akimoto T, Takasawa A, Takasawa K. et al. Estrogen/GPR30 Signaling Contributes to the Malignant Potentials of ER-Negative Cervical Adenocarcinoma via Regulation of Claudin-1 Expression. Neoplasia 2018; 20: 1083-1093 DOI: 10.1016/j.neo.2018.08.010.
    CrossrefPubMedGoogle Scholar
  • 48 Catalano S, Giordano C, Panza S. et al. Tamoxifen through GPER upregulates aromatase expression: A novel mechanism sustaining tamoxifen-resistant breast cancer cell growth. Breast Cancer Res Treat 2014; 146: 273-285 DOI: 10.1007/s10549-014-3017-4.
    CrossrefPubMedGoogle Scholar
  • 49 Lin BC, Suzawa M, Blind RD. et al. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res 2009; 69: 5415-5423 DOI: 10.1158/0008-5472.Can-08-1622.
    CrossrefPubMedGoogle Scholar
  • 50 Luo H, Yang G, Yu T. et al. GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts. Endocrine-related Cancer 2014; 21: 355-369 DOI: 10.1530/ERC-13-0237.
    CrossrefPubMedGoogle Scholar
  • 51 Kotula-Balak M, Pawlicki P, Milon A. et al. The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function-in vivo and in vitro evaluation. Cell Tissue Res 2018; 374: 389-412 DOI: 10.1007/s00441-018-2861-7.
    CrossrefPubMedGoogle Scholar
  • 52 Huang C, Yuan P, Wu J. et al. Estrogen regulates excitatory amino acid carrier 1 (EAAC1) expression through sphingosine kinase 1 (SphK1) transacting FGFR-mediated ERK signaling in rat C6 astroglial cells. Neuroscience 2016; 319: 9-22 DOI: 10.1016/j.neuroscience.2016.01.027.
    CrossrefPubMedGoogle Scholar
  • 53 Santolla MF, Vivacqua A, Lappano R. et al. GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression. Cells 2019; 8: 223 DOI: 10.3390/cells8030223.
    CrossrefPubMedGoogle Scholar
  • 54 Smith VE, Franklyn JA, McCabe CJ. Pituitary tumor-transforming gene and its binding factor in endocrine cancer. Expert Rev Mol Med 2010; 12: e38 DOI: 10.1017/s1462399410001699
    CrossrefPubMedGoogle Scholar
  • 55 Suzuki T, Sasano H, Sasaki H. et al. Quantitation of P450 aromatase immunoreactivity in human ovary during the menstrual cycle: relationship between the enzyme activity and immunointensity. Journal of Histochemistry & Cytochemistry 1994; 42: 1565-1573 DOI: 10.1177/42.12.7983357.
    CrossrefPubMedGoogle Scholar