G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth
Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometria...
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | Obstetrics and Gynecology International |
| Online Access: | http://dx.doi.org/10.1155/2013/472720 |
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| author | Whitney K. Petrie Megan K. Dennis Chelin Hu Donghai Dai Jeffrey B. Arterburn Harriet O. Smith Helen J. Hathaway Eric R. Prossnitz |
| author_facet | Whitney K. Petrie Megan K. Dennis Chelin Hu Donghai Dai Jeffrey B. Arterburn Harriet O. Smith Helen J. Hathaway Eric R. Prossnitz |
| author_sort | Whitney K. Petrie |
| collection | DOAJ |
| description | Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth. |
| format | Article |
| id | doaj-art-26a5f4cdf567496783c98a9ef452ad7c |
| institution | Kabale University |
| issn | 1687-9589 1687-9597 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Obstetrics and Gynecology International |
| spelling | doaj-art-26a5f4cdf567496783c98a9ef452ad7c2025-02-03T05:53:14ZengWileyObstetrics and Gynecology International1687-95891687-95972013-01-01201310.1155/2013/472720472720G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor GrowthWhitney K. Petrie0Megan K. Dennis1Chelin Hu2Donghai Dai3Jeffrey B. Arterburn4Harriet O. Smith5Helen J. Hathaway6Eric R. Prossnitz7Department of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Obstetrics and Gynecology, UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USADepartment of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USADepartment of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USAEndometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.http://dx.doi.org/10.1155/2013/472720 |
| spellingShingle | Whitney K. Petrie Megan K. Dennis Chelin Hu Donghai Dai Jeffrey B. Arterburn Harriet O. Smith Helen J. Hathaway Eric R. Prossnitz G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth Obstetrics and Gynecology International |
| title | G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth |
| title_full | G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth |
| title_fullStr | G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth |
| title_full_unstemmed | G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth |
| title_short | G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth |
| title_sort | g protein coupled estrogen receptor selective ligands modulate endometrial tumor growth |
| url | http://dx.doi.org/10.1155/2013/472720 |
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