title: Estrogen defines the dynamics and destination of transactivated EGF receptor in breast cancer cells: role of S1P₃ receptor and Cdc42.
abstract: Sphingosine-1-phosphate (S1P) receptors mediate transactivation of epidermal growth factor receptor (EGFR) by estrogen (E2). Here we report that the amount of intracellular EGFR remains elevated after stimulation of MCF-7 cells with E2 and S1P, although membrane-localized EGFR and S1P3 receptors are quickly internalized. Co-localization of internalized EGFR and LAMP-2 was lower in cells treated with E2/S1P, suggesting that endosomal EGFR might be directed for recycling instead of degradation. In addition, we found that E2/S1P activated Cdc42 and that knockdown of Cdc42 restores fast EGFR degradation after E2/S1P stimulation. Inhibition of S1P3 receptors prevented E2-induced activation of Cdc42, supporting the important role of the S1P receptor in E2 signaling. This is a novel mechanism further defining the effect of E2/S1P on the EGFR transactivation in breast cancer cells.
authors.affiliation: Flinders Centre for Cancer Prevention and Control, Division of Surgery, Flinders University, Bedford Park, SA 5042, Australia. olga.sukocheva@flinders.edu.au
authors.forename: O
authors.initials: O
authors.lastname: Sukocheva
authors.forename: C
authors.initials: C
authors.lastname: Wadham
authors.forename: P
authors.initials: P
authors.lastname: Xia
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D004958:Estradiol; D066246:ErbB Receptors; D020764:cdc42 GTP-Binding Protein