title: Antagonism of oestrogen action in human breast and endometrial cells in vitro: potential novel antitumour agents.
abstract: OBJECTIVE
  There is a need to find novel oestrogen receptor (ER) ligands that antagonize oestrogen action in the reproductive tissues and would therefore have therapeutic potential in oestrogen-dependent tumours. We tested novel ER ligands in both breast and endometrial cells to profile agonism/antagonism in these oestrogen target reproductive tissues.
  
  
  METHODS
  Novel analogues of the ER antagonist ICI 182,780 were synthesized and tested for their ability to inhibit gene expression dependent on oestrogen response elements (ERE) in human breast (MCF-7) and endometrial (Ishikawa) cell lines. This activity was correlated with inhibition of oestrogen-induced cell proliferation and ER binding.
  
  
  RESULTS
  The sulphide analogue (compound 1) and sulphone analogue (compound 2) had no intrinsic ERE-dependent agonism in either breast cancer or endometrial cells in culture. All three compounds dose-dependently inhibited ERE-mediated oestrogen agonism. Moreover, these ER ligands inhibited oestrogen-stimulated proliferation of breast cancer and endometrial cells. ICI 182,780, compound 1 and compound 2 were all able to bind both isoforms of the ER (ER alpha and ER beta). In endometrial cells, the relative binding to ER beta correlated with the ERE-dependent antioestrogenic effect of these ligands, suggesting that in this tissue this receptor is the predominant isoform that determines antioestrogenic activity.
  
  
  CONCLUSIONS
  The ability of these analogues of ICI 182,780 to inhibit oestrogen-stimulated transcriptional activity and cell proliferation suggests that these agents, in particular the sulphone analogue, have therapeutic potential in the treatment of breast cancer without exhibiting the unwanted oestrogenic effects in the endometrium.
authors.affiliation: Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. Mark_E_Nuttall@sbphrd.com
authors.forename: M E
authors.initials: ME
authors.lastname: Nuttall
authors.forename: I
authors.initials: I
authors.lastname: Pendrak
authors.forename: J G
authors.initials: JG
authors.lastname: Emery
authors.forename: D P
authors.initials: DP
authors.lastname: Nadeau
authors.forename: P W
authors.initials: PW
authors.lastname: Fisher
authors.forename: T A
authors.initials: TA
authors.lastname: Nicholson
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: L J
authors.initials: LJ
authors.lastname: Suva
authors.forename: W D
authors.initials: WD
authors.lastname: Kingsbury
authors.forename: M
authors.initials: M
authors.lastname: Gowen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol