title: Tamoxifen and ICI 182,780 negatively influenced cardiac cell growth via an estrogen receptor-independent mechanism.
abstract: BACKGROUND
  Recent studies have demonstrated that selective estrogen receptor modulators (SERMs) reduced identifiable risk factors implicated in cardiovascular disease. Despite this observation, the direct effect of SERMs on cardiac cell growth remains unexplored.
  
  
  METHODS
  Neonatal rat cardiac myocytes (CM) and fibroblasts (CF) were exposed to either the partial estrogen receptor agonist/antagonist 4-OH tamoxifen (e.g., SERM) or the pure estrogen receptor antagonist ICI 182,780 and the effect on DNA synthesis, cell cycle protein expression and extracellular signal-regulated kinase (ERK1/2) phosphorylation were assessed.
  
  
  RESULTS
  The treatment of CM and CF with either 4-OH tamoxifen or ICI 182,780 decreased DNA synthesis in the absence of apoptosis via an estrogen receptor-independent pathway. In CM and CF, 4-OH tamoxifen and ICI 182,780 treatment reduced proliferating cell nuclear antigen protein expression and concomitantly increased p27Kip1. 4-OH Tamoxifen and ICI 182,780 treatment increased ERK1/2 phosphorylation in CM and CF, and ERK1/2 kinase (MEK)-dependent inhibition of ERK1/2 activation attenuated ICI 182,780-mediated suppression of DNA synthesis.
  
  
  CONCLUSIONS
  These data are the first to describe cardiac cells as novel targets of SERMs and ICI 182,780, and highlight the role of the ERK1/2 pathway in the suppression of DNA synthesis.
authors.affiliation: Department of Physiology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mader
authors.forename: Angelino
authors.initials: A
authors.lastname: Calderone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077267:Fulvestrant; D020287:In Situ Nick-End Labeling; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077267:Fulvestrant; D004958:Estradiol; D004247:DNA; D020928:Mitogen-Activated Protein Kinases