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

Kogai, Takahiko; Kanamoto, Yoko; Li, Andrew; Lisa, H.; Ohashi, Emi; Taki, Katsumi; Chandraratna, Roshantha A.S.; Saito, Tsukasa; Brent, Gregory A.

doi:10.1210/en.2004-1334

Cited by 50 publications

(81 citation statements)

References 52 publications

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“…Iodide uptake assay was performed with 20 mCi/mmol Na 125 I, as described (Kogai et al 2005), with minor modifications. Briefly, cells grown in 12-well dishes were incubated for 1 h at 37 8C with 500 ml Hank's balanced salt solution (HBSS) containing w0 .…”

Section: Iodide Uptake Assaymentioning

confidence: 99%

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Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

Kogai

Sajid-Crockett

Newmarch

et al. 2008

Journal of Endocrinology

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TSH stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/phosphoinositide-3-kinase (PI3K) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of Nis mRNA by LY294002 occurred 6 h after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake (w3 . 5-fold) in BHP 2-7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2-7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.

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Section: Iodide Uptake Assaymentioning

confidence: 99%

“…Two-step quantitative RT-PCR was carried out, as described (Kogai et al 2005), with minor modifications. Briefly, total RNA was isolated by RNeasy mini kit (Qiagen) from cells grown in six-well plates.…”

Section: Reverse Transcription and Quantitative Real-time Pcr (Rt-qpcmentioning

confidence: 99%

Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

Kogai

Sajid-Crockett

Newmarch

et al. 2008

Journal of Endocrinology

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“…Therefore, expression of NIS should be considered as one of the latest events in mammary gland development because it takes place in fully differentiated mammary epithelial lactocytes. So far, transcriptional molecular elements and ligands that were hitherto shown to regulate NIS expression were identified in studies that were either carried out in experimental animals or in a rather differentiated mammary cell line, MCF-7 [1,3,5,6,[25][26][27][28][29][30][31]. Related with this, a particularity of our study is that we used a dedifferentiated tumor cell line such as MDA-MB-231 [18] in establishing the role of apo-ERa as a factor that activates NIS expression.…”

Section: Identification Of a Novel Non-canonical Ere In Nis Promotermentioning

confidence: 99%

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi¹,

Yaman²,

Demirpençe³

et al. 2006

Biochemical and Biophysical Research Communications

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The function of sodium iodide symporter (Na + /I À symporter, or NIS) in mammary epithelial cells is essential for the accumulation of I À in milk; the newborn's first source of I À for thyroid hormone synthesis. Furthermore, increased mammary gland NIS expression has previously been shown in human breast cancer. Several hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-a (ERa) positive cells and we investigated the role of ERa in the regulation of NIS expression. We showed that the suppression of endogenous ERa by RNA interference downregulates NIS expression in ERa positive mammary cells. Besides, in an ERa negative cell line, reintroduction of ERa resulted in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive element in the promoter region of NIS that specifically binds ERa and mediates ERa-dependent activation of transcription. Our results indicate that unliganded ERa (apo-ERa) contributes to the regulation of NIS gene expression. In mammary gland lactocytes, sodium/iodide (Na + /I À ) symport via NIS is required to secrete I À in mother's milk [1]. I À in milk is used by the newborn in thyroid hormone biosynthesis, and thus it plays an essential role in post-natal development of skeletal muscles, nervous system, and lungs [2]. In vivo experiments in mice have previously demonstrated that in normal physiology, NIS expression is strictly linked to mammary development in gestation, and to lactation [1]. Non-lactating mammary gland tissue in female mice does not express NIS unless animals receive subcutaneous oxytocin treatments for three consecutive days. On the other hand, a similar treatment in ovariectomized mice is not sufficient for NIS upregulation. In these surgically treated animals, administration of 17-b-estradiol (E2) together with oxytocin is essential for functional expression of NIS. The fact that E2 treatment was only essential in ovariectomized animals, whereas lactogenic hormones were sufficient for functional NIS expression in surgically untreated mice, suggested that ovary functions and endogenous estrogens are essential in upregulating NIS expression [1]. Unlike in non-lactating mammary gland tissue, in transgenic mice bearing experimental breast cancers triggered by Erb-B2/neu and ras oncogenes, functional expression of NIS significantly increases [1]. In the same study, human breast cancer specimens were also analyzed, and an increased NIS expression was detected in human invasive breast cancer and ductal carcinoma in situ, as compared to no expression of NIS in healthy breast samples obtained from reductive mammoplasty operations [1].Recent studies with an ERa+ mammary cell line model, MCF-7, have led to the identification of additional hormones or ligands that control transcriptional regulation of NIS. In this cell line, the symporter gene was shown to be indu...

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“…In contrast, the ER-negative breast cancer cell line MDA-MB 231 showed neither NIS expression nor iodide uptake, even after ATRA treatment [114]. Significant inductions of iodide uptake and NIS mRNA have been observed with isomers of ATRA, 9-cis RA and 13-cis RA [111][112][113]. ATRA and 9-cis RA stimulate formation of heterodimers of RAR and RXR and the RAR-RXR complex binds to its cis-element (retinoic acid response element (RARE)) on a target gene to stimulate or suppress transcription.…”

Section: Pharmacological Modulation Of Extrathyroidal Nis Expressionmentioning

confidence: 99%

“…The non-selective ATRA and also the isoform-selective RAR agonists have been investigated in breast cancer with the aim of inducing endogenous and functional NIS expression. Retinoids have a robust effect in inducing functional NIS in MCF-7 cells [111][112][113]. ATRA at a concentration of 1 µM has been shown to increase iodide uptake, to 10-fold above baseline, in 3 different MCF-7 sub-clones.…”

Section: Pharmacological Modulation Of Extrathyroidal Nis Expressionmentioning

confidence: 99%

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

Hingorani¹

2010

CCDT

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The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic ( 99m Tc, 125 I, 124 I) and therapeutic ( 131 I, 186 Re, 188 Re, 211 At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.

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

Cited by 50 publications

References 52 publications

Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

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