title: The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors.
abstract: OBJECTIVE
  K(+) channels play a role in the proliferation of cancer cells. We have investigated the effects of specific K(+) channel inhibitors on basal and oestrogen-stimulated proliferation of breast cancer cells.
  
  
  METHODS
  Using the mammary adenocarcinoma cell line MCF-7 we assayed cell proliferation by radiolabelled thymidine incorporation in the absence or presence of various K(+) channel inhibitors with or without 17beta-oestradiol.
  
  
  RESULTS
  Inhibitors of K(v)10.1 and K(Ca)3.1 K(+) channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K(Ca)3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3-10 microM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20-100 microM) TRAM-34 decreased cell proliferation. The enhancement of cell proliferation caused by TRAM-34 was blocked by the oestrogen receptor antagonists ICI182,780 and tamoxifen. TRAM-34 also increased progesterone receptor mRNA expression, decreased oestrogen receptor-alpha mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17beta-oestradiol.
  
  
  CONCLUSIONS
  Our results demonstrate that K(+) channels K(v)10.1 and K(Ca)3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K(Ca)3.1, directly interacts with the oestrogen receptor and mimics the effects of 17beta-oestradiol on MCF-7 cell proliferation and gene modulation. Our finding that TRAM-34 is able to activate the oestrogen receptor suggests a novel action of this supposedly specific K(+) channel inhibitor and raises concerns of interpretation in its use.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Canada. jwroy@dal.ca
authors.forename: J W
authors.initials: JW
authors.lastname: Roy
authors.forename: E A
authors.initials: EA
authors.lastname: Cowley
authors.forename: J
authors.initials: J
authors.lastname: Blay
authors.forename: P
authors.initials: P
authors.lastname: Linsdell
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002477:Cells / Q000378:metabolism / Q000473:pathology; D022082:Cellular Structures / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011720:Pyrazoles; D012333:RNA, Messenger / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C411671:TRAM 34; D013629:Tamoxifen; D004958:Estradiol; D002118:Calcium