title: Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells.
abstract: OBJECTIVE
  The sodium iodide symporter (NIS) mediates active iodide uptake in lactating breast tissue, and when its levels are enhanced by all-trans retinoic acid (atRA), NIS has been proposed as a target for the imaging and radiotherapy of breast cancer. Importantly, the estrogen receptor α (ERα) is an important regulator of atRA induced NIS gene expression in breast cancer cells. In this study, we investigated the effect of an ER agonist (17β-estradiol, E(2)) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ERα-positive breast cancer (MCF-7) model.
  
  
  METHODS
  NIS functional activity was measured in vitro by (125)I uptake assay after incubation with E(2) (from 10(-15) to 10(-5) M), TOT (from 5×10(-8) to 5×10(-6) M), or RAL (from 5×10(-8) to 5×10(-6) M) in the presence or absence of atRA (10(-7) M). Under the same conditions, NIS mRNA expression was examined by reverse transcriptase polymerase chain reaction. Athymic mice with MCF-7 xenograft tumors were treated with atRA alone or atRA together with E(2) to evaluate the change of (125)I uptake in tumor tissues in vivo.
  
  
  RESULTS
  In the iodide uptake study in cells, E(2), TOT, or RAL treatment alone did not stimulate (125)I uptake. However, when iodide uptake was stimulated by atRA, cotreatment with E(2), TOT or RAL decreased (125)I uptake in a concentration-dependent manner. The hormone effects on NIS mRNA expression levels in MCF-7 cells were similar. The results of the in vivo biodistribution study showed that (125)I uptake was reduced 50% in tumor tissues of mice treated with atRA/E(2) as compared to tumors treated only with atRA.
  
  
  CONCLUSIONS
  Our results suggest that combination treatment of atRA and ER ligands could limit the functional activity of the NIS gene induced by atRA, thereby compromising its use as a target for diagnosis or radiotherapy in breast cancer.
authors.affiliation: Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Cheong
authors.forename: DooRye
authors.initials: D
authors.lastname: Jang
authors.forename: Hwan-Jeong
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Seok Tae
authors.initials: ST
authors.lastname: Lim
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Sohn
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027981:Symporters / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D004958:Estradiol; D007457:Iodine Radioisotopes; D008024:Ligands; D012333:RNA, Messenger; D020849:Raloxifene Hydrochloride; D011960:Receptors, Estrogen; D027981:Symporters; D013629:Tamoxifen; D014212:Tretinoin; D000099209:Sodium-Iodide Symporters; C016601:afimoxifene