Effect of ligands of nuclear hormone receptors on sodium/iodide symporter expression and activity in breast cancer cells.
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.
Tanosaki
Sakae
S
Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Research Institute, University of California-Los Angeles School of Medicine, Los Angeles, CA 90048, USA. stanosaki@aol.com
Ikezoe
Takayuki
T
Heaney
Anthony
A
Said
Jonathan W
JW
Dan
Kazuo
K
Akashi
Makoto
M
Koeffler
H Phillip
HP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007455:Iodine / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D009362:Neoplasm Metastasis / Q000000981:diagnostic imaging; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011877:Radionuclide Imaging; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000096:biosynthesis*; D014157:Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D000970:Antineoplastic Agents; D007455:Iodine; D007457:Iodine Radioisotopes; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D027981:Symporters; D014157:Transcription Factors; D014212:Tretinoin; D000099209:Sodium-Iodide Symporters