title: Global profiling of TSEC proliferative potential by the use of a reporter mouse for proliferation.
abstract: BACKGROUND
  "Tissue-selective estrogen complex" or TSEC is a novel concept of estrogen replacement therapy for the postmenopause based on the combined use of estrogens and selective estrogen receptor modulators (SERMs). The aim of this study was to exploit the potential of a novel transgenic mouse where luciferase expression is associated with cell proliferation (the MITO-luc mouse) to investigate cell proliferation in reproductive and nonreproductive tissues in mice exposed to repetitive treatments with TSEC.
  
  
  METHODS
  Ovariectomized MITO-Luc mice were subjected to a daily oral treatment with bazedoxifene, conjugated estrogen (CE), TSEC, or raloxifene for 21 days. During the treatment, the proliferative effects of treatments were monitored by bioluminescence-based in vivo imaging. At the end of the treatment, mice were euthanized and cell proliferation assessed in selected tissues by quantitative analysis of luciferase activity and by immunohistochemistry (IHC).
  
  
  RESULTS
  In uterus treatment with CE, but not TSEC, induced a large increase in luciferase activity underlying the proliferative effect of the hormone. No accumulation of luciferase was observed in other organs and tissues target of estrogen action. We observed an increase of Ki67 immunoreactivity only in the uterus of mice treated with CE.
  
  
  CONCLUSIONS
  Pairing of an SERM with estrogens results in a complete blockage of CE proliferative effects in uterus and the absence of any undesired proliferative effects in other organs; moreover, the MITO-Luc mouse is an efficacious tool for the global, rapid, and reliable analysis of drug-induced proliferation.
authors.affiliation: TOP srl, Transgenic Operative Products, Lodi, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Oliva
authors.forename: Chiara
authors.initials: C
authors.lastname: Roncoroni
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.forename: Electra
authors.initials: E
authors.lastname: Brunialti
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Rizzi
authors.forename: Marcella
authors.initials: M
authors.lastname: De Maglie
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Giulia
authors.initials: G
authors.lastname: Piaggio
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
authors.forename: Barry
authors.initials: B
authors.lastname: Komm
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D017930:Genes, Reporter / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D004966:Estrogens, Conjugated (USP); D020845:Selective Estrogen Receptor Modulators