Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells

Endocrinology. 2008 Aug;149(8):3799-808. doi: 10.1210/en.2008-0117. Epub 2008 May 8.


Different cellular receptors mediate the biological effects induced by estrogens. In addition to the classical nuclear estrogen receptors (ERs)-alpha and -beta, estrogen also signals through the seven-transmembrane G-protein-coupled receptor (GPR)-30. Using as a model system SkBr3 and BT20 breast cancer cells lacking the classical ER, the regulation of GPR30 expression by 17beta-estradiol, the selective GPR30 ligand G-1, IGF-I, and epidermal growth factor (EGF) was evaluated. Transient transfections with an expression plasmid encoding a short 5'-flanking sequence of the GPR30 gene revealed that an activator protein-1 site located within this region is required for the activating potential exhibited only by EGF. Accordingly, EGF up-regulated GPR30 protein levels, which accumulated predominantly in the intracellular compartment. The stimulatory role elicited by EGF on GPR30 expression was triggered through rapid ERK phosphorylation and c-fos induction, which was strongly recruited to the activator protein-1 site found in the short 5'-flanking sequence of the GPR30 gene. Of note, EGF activating the EGF receptor-MAPK transduction pathway stimulated a regulatory loop that subsequently engaged estrogen through GPR30 to boost the proliferation of SkBr3 and BT20 breast tumor cells. The up-regulation of GPR30 by ligand-activated EGF receptor-MAPK signaling provides new insight into the well-known estrogen and EGF cross talk, which, as largely reported, contributes to breast cancer progression. On the basis of our results, the action of EGF may include the up-regulation of GPR30 in facilitating a stimulatory role of estrogen, even in ER-negative breast tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Flanking Region / genetics
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / physiology
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Molecular Sequence Data
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / genetics*
  • Signal Transduction / physiology
  • Transcription Factor AP-1 / metabolism
  • Transfection
  • Up-Regulation / drug effects


  • GPER1 protein, human
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Transcription Factor AP-1
  • Epidermal Growth Factor
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases