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

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, E₂) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ERβ-positive breast cancer (MCF-7) model. Methods: NIS functional activity was measured in vitro by ¹²⁵I uptake assay after incubation with E₂ (from 10^β15 to 10^β5 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 E₂ to evaluate the change of ¹²⁵I uptake in tumor tissues in vivo. Results: In the iodide uptake study in cells, E₂, TOT, or RAL treatment alone did not stimulate ¹²⁵I uptake. However, when iodide uptake was stimulated by atRA, cotreatment with E₂, TOT or RAL decreased ¹²⁵I 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 ¹²⁵I uptake was reduced 50% in tumor tissues of mice treated with atRA/E₂ 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.