scholarly journals Differential Regulation of Sodium/Iodide Symporter Gene Expression by Nuclear Receptor Ligands in MCF-7 Breast Cancer Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3059-3069 ◽  
Author(s):  
Takahiko Kogai ◽  
Yoko Kanamoto ◽  
Andrew I. Li ◽  
Lisa H. Che ◽  
Emi Ohashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Receptor Ligands ◽  
Iodide Uptake ◽  
Nuclear Receptor Ligands ◽  
Mcf 7 ◽  
Stimulation Of

Abstract The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of β-emitting radioiodide-131 (131I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance 131I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) β/γ produced marked NIS induction; and selective stimulation of RARα, RARγ, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR β/γ-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC50 of tRA for NIS stimulation to approximately 7%, such that 10 −7m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of 131I greater than 10−6m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of 131I after combination treatment.

scholarly journals Transcription Factor Nkx-2.5 Induces Sodium/Iodide Symporter Gene Expression and Participates in Retinoic Acid- and Lactation-Induced Transcription in Mammary Cells

2004 ◽  
Vol 24 (18) ◽  
pp. 7863-7877 ◽  
Author(s):  
Monica Dentice ◽  
Cristina Luongo ◽  
Antonia Elefante ◽  
Romina Romino ◽  
Raffaele Ambrosio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Retinoic Acid ◽  
Sodium Iodide ◽  
Molecular Mechanisms ◽  
Mammary Cells ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Potent Inducer ◽  
Mcf 7

ABSTRACT The sodium/iodide symporter (NIS) is a plasma membrane protein that mediates active iodide transport in thyroid and mammary cells. It is a prerequisite for radioiodide treatment of thyroid cancer and a promising diagnostic and therapeutic tool for breast cancer. We investigated the molecular mechanisms governing NIS expression in mammary cells. Here we report that Nkx-2.5, a cardiac homeobox transcription factor that is also expressed in the thyroid primordium, is a potent inducer of the NIS promoter. By binding to two specific promoter sites (N2 and W), Nkx-2.5 induced the rNIS promoter (about 50-fold over the basal level). Interestingly, coincident with NIS expression, Nkx-2.5 mRNA and protein were present in lactating, but not virgin, mammary glands in two human breast cancer samples and in all-trans retinoic acid (tRA)-stimulated MCF-7 breast cancer cells. A cotransfected dominant-negative Nkx-2.5 mutant abolished tRA-induced endogenous NIS induction, which shows that Nkx-2.5 activity is critical for this process. Remarkably, in MCF-7 cells, Nkx-2.5 overexpression alone was sufficient to induce NIS and iodide uptake. In conclusion, Nkx-2.5 is a novel relevant transcriptional regulator of mammary NIS and could thus be exploited to manipulate NIS expression in breast cancer treatment strategies.

scholarly journals Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells

2006 ◽  
Vol 91 (1) ◽  
pp. 69-78 ◽  
Author(s):  
S. Unterholzner ◽  
M. J. Willhauck ◽  
N. Cengic ◽  
M. Schütz ◽  
B. Göke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Sodium Iodide ◽  
Clonogenic Assay ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Mcf 7

Abstract Context: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine. Objective: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells. Design: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10−9 to 10−7m) in the presence of atRA (10−6m) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay. Results: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA. Conclusion: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells.

scholarly journals Regulation of Iodide Uptake and Sodium/Iodide Symporter Expression in the MCF-7 Human Breast Cancer Cell Line

2005 ◽  
Vol 90 (4) ◽  
pp. 2321-2326 ◽  
Author(s):  
Franco Arturi ◽  
Elisabetta Ferretti ◽  
Ivan Presta ◽  
Tiziana Mattei ◽  
Angela Scipioni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Human Breast Cancer ◽  
Sodium Iodide ◽  
Cancer Cell Line ◽  
Human Breast Cancer Cell ◽  
Sodium Iodide Symporter ◽  
Human Breast ◽  
Iodide Uptake ◽  
Mcf 7

scholarly journals Hydrocortisone and Purinergic Signaling Stimulate Sodium/Iodide Symporter (NIS)-Mediated Iodide Transport in Breast Cancer Cells

2006 ◽  
Vol 20 (5) ◽  
pp. 1121-1137 ◽  
Author(s):  
Orsolya Dohán ◽  
Antonio De la Vieja ◽  
Nancy Carrasco
Keyword(s):  
Breast Cancer ◽  
Thyroid Cancer ◽  
Protein Expression ◽  
Therapeutic Efficacy ◽  
Sodium Iodide ◽  
Purinergic Signaling ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Mcf 7

Abstract The sodium/iodide symporter (NIS) mediates a remarkably effective targeted radioiodide therapy in thyroid cancer; this approach is an emerging candidate for treating other cancers that express NIS, whether endogenously or by exogenous gene transfer. Thus far, the only extrathyroidal malignancy known to express functional NIS endogenously is breast cancer. Therapeutic efficacy in thyroid cancer requires that radioiodide uptake be maximized in tumor cells by manipulating well-known regulatory factors of NIS expression in thyroid cells, such as TSH, which stimulates NIS expression via cAMP. Similarly, therapeutic efficacy in breast cancer will likely depend on manipulating NIS regulation in mammary cells, which differs from that in the thyroid. Human breast adenocarcinoma MCF-7 cells modestly express endogenous NIS when treated with all-trans-retinoic acid (tRa). We report here that hydrocortisone and ATP each markedly stimulates tRa-induced NIS protein expression and plasma membrane targeting in MCF-7 cells, leading to at least a 100% increase in iodide uptake. Surprisingly, the adenyl cyclase activator forskolin, which promotes NIS expression in thyroid cells, markedly decreases tRa-induced NIS protein expression in MCF-7 cells. Isobutylmethylxanthine increases tRa-induced NIS expression in MCF-7 cells, probably through a purinergic signaling system independent of isobutylmethylxanthine’s action as a phosphodiesterase inhibitor. We also observed that neither iodide, which at high concentrations down-regulates NIS in the thyroid, nor cAMP has a significant effect on NIS expression in MCF-7 cells. Our findings may open new strategies for breast-selective pharmacological modulation of functional NIS expression, thus improving the feasibility of using radioiodide to effectively treat breast cancer.

Stimulation of retinoic acid-induced functional sodium iodide symporter (NIS) expression and cytotoxicity of 131I by carbamazepine in breast cancer cells

2010 ◽  
Vol 125 (2) ◽  
pp. 377-386 ◽  
Author(s):  
Michael J. Willhauck ◽  
Dennis J. O`Kane ◽  
Nathalie Wunderlich ◽  
Burkhard Göke ◽  
Christine Spitzweg
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Stimulation Of

scholarly journals Retinoic Acid Stimulation of the Sodium/Iodide Symporter in MCF-7 Breast Cancer Cells Is Meditated by the Insulin Growth Factor-I/Phosphatidylinositol 3-Kinase and p38 Mitogen-Activated Protein Kinase Signaling Pathways

2008 ◽  
Vol 93 (5) ◽  
pp. 1884-1892 ◽  
Author(s):  
Takahiko Kogai ◽  
Emi Ohashi ◽  
Megan S. Jacobs ◽  
Saima Sajid-Crockett ◽  
Myrna L. Fisher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Breast Cancer Cells ◽  
Sodium Iodide Symporter ◽  
Phosphatidylinositol 3 Kinase ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Igf I ◽  
Nis Gene ◽  
Mcf 7

Abstract Context: All-trans retinoic acid (tRA) induces differentiation in MCF-7 breast cancer cells, stimulates sodium/iodide symporter (NIS) gene expression, and inhibits cell proliferation. Radioiodine administration after systemic tRA treatment has been proposed as an approach to image and treat some differentiated breast cancer. Objective: The objective of this work was to study the relative role of genomic and nongenomic pathways in tRA stimulation of NIS expression in MCF-7 cells. Design: We inspected the human NIS gene locus for retinoic acid-responsive elements and tested them for function. The effects of signal transduction pathway inhibitors were also tested in tRA-treated MCF-7 cells and TSH-stimulated FRTL-5 rat thyroid cells, followed by iodide uptake assay, quantitative RT-PCR of NIS, and cell cycle phase analysis. Results: Multiple retinoic acid response elements around the NIS locus were identified by sequence inspection, but none of them was a functional tRA-induced element in MCF-7 cells. Inhibitors of the IGF-I receptor, Janus kinase, and phosphatidylinositol 3-kinase (PI3K), significantly reduced NIS mRNA expression and iodide uptake in tRA-stimulated MCF-7 cells but not FRTL-5 cells. An inhibitor of p38 MAPK significantly reduced iodide uptake in both tRA-stimulated MCF-7 cells and TSH-stimulated FRTL-5 cells. IGF-I and PI3K inhibitors did not significantly reduce the basal NIS mRNA expression in MCF-7 cells. Despite the chronic inhibitory effects on cell proliferation, tRA did not reduce the S-phase distribution of MCF-7 cells during the period of NIS induction. Conclusion: The IGF-I receptor/PI3K pathway mediates tRA-stimulated NIS expression in MCF-7 but not FRTL-5 thyroid cells.

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