G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

Author:

Petrie Whitney K.1,Dennis Megan K.1,Hu Chelin1ORCID,Dai Donghai23,Arterburn Jeffrey B.4,Smith Harriet O.125,Hathaway Helen J.1,Prossnitz Eric R.1

Affiliation:

1. Department of Cell Biology and Physiology and UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

2. Department of Obstetrics and Gynecology, UNM Cancer Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

3. Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

4. Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA

5. Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA

Abstract

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 ERαand 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 activityin vivoprevents estrogen-mediated tumor growth.

Funder

National Institutes of Health

Publisher

Hindawi Limited

Subject

Obstetrics and Gynaecology

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