Effect of ligands of nuclear hormone receptors on sodium/iodide symporter expression and activity in breast cancer cells

Breast Cancer Res Treat. 2003 Jun;79(3):335-45. doi: 10.1023/a:1024064424855.


Iodide uptake by normal and cancerous thyroid cells is an active process mediated by the sodium/iodide symporter (NIS). Using quantitative real-time RT-PCR, we found that all 22 fresh human breast cancer samples had very low NIS expression similar to levels in untreated MCF-7 breast cancer cells. 9-cis retinoic acid (9-cis RA), a ligand for both retinoic acid receptor (RAR)/retinoic X receptor (RXR) heterodimers as well as RXR/RXR homodimers, markedly induced NIS mRNA expression in MCF-7 breast cancer cells in a dose- and time-dependent fashion, with maximal levels occurring at 12 h. All-trans retinoic acid, ATRA, a RAR specific ligand had a similar potency. Among eight breast cancer cell lines, three out of four estrogen receptor (ER)-positive and zero of four ER-negative cell lines responded to 9-cis RA by increasing their expression of NIS. Combining a RAR with a RXR selective ligand enhanced both NIS mRNA expression and iodide uptake in MCF-7 cells. Similarly, a ligand for proliferator-activated receptor gamma (PPARgamma) when combined with 9-cis RA synergistically increased both NIS mRNA levels and iodide uptake in these MCF-7 cells. The iodide uptake was blocked by KClO4. In conclusions, these findings suggest that selected combinations of NHR ligands should be examined in a limited trial to determine if their administration to patients allows the use of radioactive iodine for diagnosis and possibly treatment of metastatic breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Female
  • Humans
  • Iodine / pharmacokinetics
  • Iodine Radioisotopes / pharmacokinetics
  • Ligands
  • Neoplasm Metastasis / diagnostic imaging
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Radionuclide Imaging
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Retinoic Acid / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Symporters / biosynthesis*
  • Transcription Factors / physiology*
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Iodine Radioisotopes
  • Ligands
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Symporters
  • Transcription Factors
  • sodium-iodide symporter
  • Tretinoin
  • Iodine