title: Interactions between MAP kinase and oestrogen receptor in human breast cancer.
abstract: OBJECTIVE
  The oestrogen receptor (ERα) may be activated in a ligand-dependent manner, via oestrogen, or in a ligand-independent manner, via signal transduction pathways. Mitogen Activated Protein Kinase (MAPK) is known to directly phosphorylate ERα at serine 118 in a ligand-independent manner. This study investigated the interaction between MAPK and ERα in breast cancer.
  
  
  METHODS
  Immunohistochemical experiments were undertaken to determine the expression of MAPK, pMAPK and pER(ser118) in breast tumours to determine their clinical relevance. Immunofluorescent experiments were performed, on MCF-7 breast cancer cells, to monitor the phosphorylation and localisation of MAPK and ERα in response to oestrogen, heregulin and a MAPK inhibitor.
  
  
  RESULTS
  Oestrogen and Heregulin stimulated phosphorylation of ERα and its nuclear translocation, but heregulin induced this at levels much lower than those observed with oestrogen. Following stimulation with heregulin, but not oestrogen, treatment with MAPK inhibitor reduced the levels of nuclear pER(ser118). In cells treated with both oestrogen and heregulin, nuclear pER(ser118) was visible; but at levels comparable with heregulin treatment alone.
  
  
  CONCLUSIONS
  This study confirms that ligand-mediated phosphorylation is associated with rapid nuclear localisation of ERα, due to oestrogen binding. ERα is phosphorylated at serine 118 in a ligand-independent manner. Preventing nuclear translocation of pMAPK reduced the levels of ligand-independent, but not ligand-dependent phosphorylation of ERα. Co-stimulation with both oestrogen and heregulin suggested that heregulin mediated signalling determines the subcellular localisation of ERα. Activation of ERα by direct phosphorylation may result in its rapid deactivation due to degradation or nuclear export.
authors.affiliation: Institute of Cancer Sciences, College of MVLS, University of Glasgow, Western Infirmary, Glasgow G11 6NT, UK. liane.mcglynn@glasgow.ac.uk
authors.forename: Liane M
authors.initials: LM
authors.lastname: McGlynn
authors.forename: Sian
authors.initials: S
authors.lastname: Tovey
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Julie
authors.initials: J
authors.lastname: Doughty
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cooke
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism*; D013997:Time Factors
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020890:Neuregulin-1; D012694:Serine; D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases