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G Protein–Coupled Receptor 30 (GPR30) Mediates Gene Expression Changes and Growth Response to 17ß-Estradiol and Selective GPR30 Ligand G-1 in Ovarian Cancer Cells

Departments of ¹ Pharmaco-Biology and ² Cell Biology, University of Calabria, Rende (Cosenza), Italy and ³ Division of Biocomputing, ⁴ Department of Cell Biology and Physiology, and ⁵ Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico

Requests for reprints: Marcello Maggiolini, Department of Pharmaco-Biology, University of Calabria, 87030 Rende (Cosenza), Italy. Phone: 39-09-84493076; Fax: 39-09-84493271; E-mail: marcellomaggiolini{at}yahoo.it.

Estrogens play a crucial role in the development of ovarian tumors; however, the signal transduction pathways involved in hormone action are still poorly defined. The orphan G protein–coupled receptor 30 (GPR30) mediates the nongenomic signaling of 17ß-estradiol (E2) in a variety of estrogen-sensitive cancer cells through activation of the epidermal growth factor receptor (EGFR) pathway. Whether estrogen receptor (ER) also contributes to GPR30/EGFR signaling is less understood. Here, we show that, in ER-positive BG-1 ovarian cancer cells, both E2 and the GPR30-selective ligand G-1 induced c-fos expression and estrogen-responsive element (ERE)-independent activity of a c-fos reporter gene, whereas only E2 stimulated an ERE-responsive reporter gene, indicating that GPR30 signaling does not activate ER-mediated transcription. Similarly, both ligands up-regulated cyclin D1, cyclin E, and cyclin A, whereas only E2 enhanced progesterone receptor expression. Moreover, both GPR30 and ER expression are required for c-fos stimulation and extracellular signal-regulated kinase (ERK) activation in response to either E2 or G-1. Inhibition of the EGFR transduction pathway inhibited c-fos stimulation and ERK activation by either ligand, suggesting that in ovarian cancer cells GPR30/EGFR signaling relays on ER expression. Interestingly, we show that both GPR30 and ER expression along with active EGFR signaling are required for E2-stimulated and G-1–stimulated proliferation of ovarian cancer cells. Because G-1 was able to induce both c-fos expression and proliferation in the ER-negative/GPR30-positive SKBR3 breast cancer cells, the requirement for ER expression in GPR30/EGFR signaling may depend on the specific cellular context of different tumor types. [Cancer Res 2007;67(4):1859–66]

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