Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells.

Abstract

PURPOSE:

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.

CONCLUSION:

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: Su-Jin Cheong, DooRye Jang, Hwan-Jeong Jeong, Seok Tae Lim, Myung-Hee Sohn, John A Katzenellenbogen, Dong Wook Kim
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 38 Issue 2 Pg. 287-94 (Feb 2011) ISSN: 1872-9614 [Electronic] United States
• PMID: 21315285 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Iodine Radioisotopes
• Ligands
• RNA, Messenger
• Receptors, Estrogen
• Symporters
• Tamoxifen
• afimoxifene
• Raloxifene Hydrochloride
• Estradiol
• sodium-iodide symporter
• Tretinoin

Topics

• Animals
• Biological Transport (drug effects)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Interactions
• Estradiol (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Iodine Radioisotopes (metabolism, pharmacokinetics)
• Ligands
• Mice
• Mice, Inbred BALB C
• RNA, Messenger (genetics, metabolism)
• Raloxifene Hydrochloride (pharmacology)
• Receptors, Estrogen (agonists, antagonists & inhibitors, metabolism)
• Symporters (genetics)
• Tamoxifen (analogs & derivatives, pharmacology)
• Tretinoin (pharmacology)
• Xenograft Model Antitumor Assays