title: EGR1 expression: a calcium and ERK1/2 mediated PPARγ-independent event involved in the antiproliferative effect of 15-deoxy-Δ12,14-prostaglandin J2 and thiazolidinediones in breast cancer cells.
abstract: Our aim was to get new information about the Peroxisome Proliferator Activated Receptor gamma (PPARγ)-independent pathway involved in the antiproliferative action of PPARγ ligands in breast cancer cells. We investigated the effects of Troglitazone (TGZ), Ciglitazone (CGZ), Rosiglitazone (RGZ) and, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ(2)) on the hormone-dependent breast cancer cell line MCF7. The early transcription factor EGR1 (Early Growth Response gene 1) mRNA and protein levels peaked after 3h of incubation with 25μM TGZ, CGZ or 15d-PGJ(2) and then gradually decreased. RGZ, the most potent activator of PPARγ, did not show this effect. The PPARγ antagonist GW 9662 did not block EGR1 mRNA induction which also still occurred in case of PPARγ silencing as well as in case of treatment with the PPARγ-inactive compound Δ2-TGZ. EGR1 mRNA induction required ERK1/2 phosphorylation which was not blocked by EGF Receptor (EGFR) inhibition. The ERK1/2 pathway was also involved in Δ2-TGZ-induced EGR1 mRNA expression in the hormone-independent breast cancer cell line MDA-MB-231. Using the fluorescent dye Fura2, we showed in MCF7 that TGZ or Δ2-TGZ induced an immediate increase in cytosolic calcium which was required for ERK1/2 phosphorylation and EGR1 mRNA induction as demonstrated by calcium chelation experiments. Furthermore, in MCF7 transfected with siRNA targeting EGR1, Δ2-TGZ inhibited less efficiently cell proliferation.
authors.affiliation: EA4421 Signalisation, Génomique et Recherche Translationnelle en Oncologie (SIGRETO) Nancy-Université, 54506 Vandœuvre-lès-Nancy, France.
authors.forename: Sarra
authors.initials: S
authors.lastname: Chbicheb
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Rodeau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Salamone
authors.forename: Michel
authors.initials: M
authors.lastname: Boisbrun
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
authors.forename: Daniel
authors.initials: D
authors.lastname: Spohn
authors.forename: Isabelle
authors.initials: I
authors.lastname: Grillier-Vuissoz
authors.forename: Yves
authors.initials: Y
authors.lastname: Chapleur
authors.forename: Stéphane
authors.initials: S
authors.lastname: Flament
authors.forename: Sabine
authors.initials: S
authors.lastname: Mazerbourg
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005260:Female; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017931:DNA Primers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D047495:PPAR gamma; D045162:Thiazolidinediones; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015230:Prostaglandin D2; D002118:Calcium