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.
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.
Filardo
Edward J
EJ
Department of Medicine, Division of Clinical Pharmacology, Rhode Island Hospital and Brown University, Aldrich Bldg Rm 718, 593 Eddy Street, Providence, RI 02903, USA. edward.filardo@brown.edu
D001943:Breast Neoplasms / Q000235:genetics*; D066246:ErbB Receptors / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics*; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction; D015533:Transcriptional Activation
D004967:Estrogens; C109584:GPER1 protein, human; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D066246:ErbB Receptors; D019204:GTP-Binding Proteins