Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer

J Steroid Biochem Mol Biol. 2002 Feb;80(2):231-8. doi: 10.1016/s0960-0760(01)00190-x.


The biological and biochemical effects of estrogen have been ascribed to its known receptors, which function as ligand-inducible transcription factors. However, estrogen also triggers rapid activation of classical second messengers (cAMP, calcium, and inositol triphosphate) and stimulation of intracellular signaling cascades mitogen-activated protein kinase (MAP K), PI3K and eNOS. These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins. We have shown that estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via the G-protein-coupled receptor (GPCR), GPR30, through the release of surface-bound proHB-EGF from estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling. GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the EGF-like effects of estrogen. This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Breast Neoplasms / genetics*
  • ErbB Receptors / physiology*
  • Estrogens / physiology*
  • Female
  • GTP-Binding Proteins / genetics
  • Humans
  • MAP Kinase Signaling System / physiology
  • Receptors, Cell Surface / genetics*
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled*
  • Signal Transduction
  • Transcriptional Activation


  • Estrogens
  • GPER1 protein, human
  • Receptors, Cell Surface
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • ErbB Receptors
  • GTP-Binding Proteins