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.