title: Effects of ospemifene, a novel selective estrogen-receptor modulator, on human breast tissue ex vivo.
abstract: Ospemifene (Osp) is a novel selective estrogen-receptor modulator (SERM) accepted for the treatment of dyspareunia, a symptom of postmenopausal vulvovaginal atrophy. We aimed to analyze the effects of Osp on human breast tissue (HBT), in comparison with the clinically established SERMs raloxifene (Ral) and tamoxifen (Tam), using ex vivo explant cultures.
  
  
  
  HBT samples were obtained from postmenopausal women undergoing mammoplasty and cultured with or without Osp, Ral, Tam, or 17β-estradiol (E2) for 7 and 14 days, and studied for morphology, proliferation, and apoptosis. The expression of epithelial markers, the estrogen-receptor alpha (ERα), the androgen receptor (AR), TFF1, and apolipoprotein D was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The PvuII polymorphism of ERS1 was determined.
  
  
  
  Osp, similar to Ral and Tam, decreased the number of proliferating cells in a concentration-dependent manner (at 100 nM, P < 0.01) and strongly opposed 10 nM E2-stimulated proliferation (P < 0.001). Corresponding effects were observed in the proportions of cells expressing ERα and TFF1 (P < 0.001). At 14 days apoptosis was increased by 100 nM SERMs (P < 0.01), but, notably, decreased by 1 nM Osp and Ral at day 7 (P < 0.05). The SERMs exerted ER-agonist effects on AR-positive cell populations at 1 nM (P < 0.05), but not at 100 nM concentrations. The effects on proliferation and ERα expressing cell numbers were associated with the ERS1 PvuII genotype.
  
  
  
  In summary, Osp inhibited proliferation and opposed E2 stimulation in normal HBT in an efficacious, but less potent way than Ral and Tam. The ESR1 PvuII polymorphisms may influence the responsiveness of HBT to E2 and SERMs.
authors.affiliation: 1Department of Cell Biology and Anatomy, Institute of Biomedicine 2Department of Biostatistics, University of Turku, Finland 3Hormos Ltd, Turku, Finland 4IMC FH Krems, Austria 5Department of Obstetrics and Gynaecology, Turku University Central Hospital, Finland.
authors.forename: Natalija
authors.initials: N
authors.lastname: Eigeliene
authors.forename: Lauri
authors.initials: L
authors.lastname: Kangas
authors.forename: Christina
authors.initials: C
authors.lastname: Hellmer
authors.forename: Tommi
authors.initials: T
authors.lastname: Kauko
authors.forename: Risto
authors.initials: R
authors.lastname: Erkkola
authors.forename: Pirkko
authors.initials: P
authors.lastname: Härkönen
mesh_terms: D000368:Aged; D053399:Apolipoproteins D / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause / Q000187:drug effects*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071163:Trefoil Factor-1 / Q000378:metabolism
chemical_list: C024328:APOD protein, human; C410798:AR protein, human; D053399:Apolipoproteins D; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D020845:Selective Estrogen Receptor Modulators; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; C119141:Ospemifene