G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Academic Article uri icon

start page

  • 1859

end page

  • 1866

abstract

  • 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 17beta-estradiol (E2) in a variety of estrogen-sensitive cancer cells through activation of the epidermal growth factor receptor (EGFR) pathway. Whether estrogen receptor alpha (ERalpha) also contributes to GPR30/EGFR signaling is less understood. Here, we show that, in ERalpha-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 ERalpha-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 ERalpha 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 ERalpha expression. Interestingly, we show that both GPR30 and ERalpha 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 ERalpha-negative/GPR30-positive SKBR3 breast cancer cells, the requirement for ERalpha expression in GPR30/EGFR signaling may depend on the specific cellular context of different tumor types.

date/time value

  • 2007

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-06-2909

PubMed Identifier

  • 17308128

volume

  • 67

number

  • 4

keywords

  • Animals
  • Breast Neoplasms
  • Cell Growth Processes
  • Cell Line, Tumor
  • Cyclopentanes
  • Estradiol
  • Estrogen Receptor alpha
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, fos
  • Humans
  • Ovarian Neoplasms
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos
  • Quinolines
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Signal Transduction