title: The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells.
abstract: A growing body of evidence concerning estrogen effects cannot be explained by the classic model of hormone action, which involves the binding to estrogen receptors (ERs) alpha and ERbeta and the interaction of the steroid-receptor complex with specific DNA sequences associated with target genes. Using c-fos proto-oncogene expression as an early molecular sensor of estrogen action in ERalpha-positive MCF7 and ER-negative SKBR3 breast cancer cells, we have discovered that 17beta-estradiol (E2), and the two major phytoestrogens, genistein and quercetin, stimulate c-fos expression through ERalpha as well as through an ER-independent manner via the G protein-coupled receptor homologue GPR30. The c-fos response is repressed in GPR30-expressing SKBR3 cells transfected with an antisense oligonucleotide against GPR30 and reconstituted in GPR30-deficient MDA-MB 231 and BT-20 breast cancer cells transfected with a GPR30 expression vector. GPR30-dependent activation of ERK1/2 by E2 and phytoestrogens occurs via a Gbetagamma-associated pertussis toxin-sensitive pathway that requires both Src-related and EGF receptor tyrosine kinase activities. The ability of E2 and phytoestrogens to regulate the expression of growth-related genes such as c-fos even in the absence of ER has interesting implications for understanding breast cancer progression.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, 87030 Rende (CS), Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fasanella
authors.forename: Anna Grazia
authors.initials: AG
authors.lastname: Recchia
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Montanaro
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Musti
authors.forename: Didier
authors.initials: D
authors.lastname: Picard
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D048789:Phytoestrogens; D028321:Plant Preparations / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011794:Quercetin / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; D007529:Isoflavones; C000715470:MAS1 protein, human; D020320:Oligoribonucleotides, Antisense; D048789:Phytoestrogens; D028321:Plant Preparations; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D011794:Quercetin; D019833:Genistein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases