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Departments of Surgery (I.L.W., R.S.G.) and Pathology (M.v.d.R., K.N., K.M.), Stanford University School of Medicine, Stanford, California 94305-5655; Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (P.S.A., K.W.), New Brunswick, New Jersey 08903; and Department of Molecular Pharmacology, Albert Einstein College of Medicine (O.D., N.C.), Bronx, New York 10461
Address all correspondence and requests for reprints to: Irene L. Wapnir, M.D., Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, H-3625, Stanford, California 94305-5655. E-mail: wapnir{at}stanford.edu.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cloning of rat (2) and human (17) NIS cDNAs and subsequent generation of anti-NIS antibodies (Ab) have made it possible to examine NIS expression in human tissues and correlate it with I- uptake (4, 18, 19, 20, 21, 22). NIS is a transmembrane glycoprotein located in the basolateral plasma membrane of thyrocytes, gastric mucosa, salivary glands, and lactating mammary cells. To date, NIS transcripts have been detected by RT-PCR, Northern blotting, or Southern hybridization in the thyroid, salivary gland, pituitary gland, pancreas, testis, mammary gland, gastric mucosa, colon, ovary, prostate, adrenal glands, heart, thymus, omentum, gallbladder, and lung (23, 24, 25, 26). NIS protein, on the other hand, was initially identified in fewer tissues, namely thyroid, salivary gland, stomach, and mammary gland (4, 20, 21). Subsequent immunohistochemical studies have shown that pancreas, colonic mucosa, lacrimal glands, placenta, and renal tubular cells can be added to the list of NIS protein-expressing tissues (22, 27, 28, 29).
I- transport occurs in a majority of thyroid carcinomas and thus is used therapeutically to selectively deliver 131I and ablate tumors. Consistent with these clinical observations, over 70% of differentiated thyroid cancers (DTC) express NIS, even though most malignant masses appear as scintigraphically cold nodules; i.e. they take up less radioiodide or pertechnetate than normal thyroid tissue (30, 31, 32, 33).
An important recent discovery was that NIS is functionally expressed in vivo in transgenic mouse mammary tumors and is immunohistochemically detected in over 80% of human breast cancers (4), raising the possibility of using radioiodide as a novel therapy in breast cancer. Other iodide-transporting tissues also may up-regulate NIS in the process of malignant transformation. It is therefore arguable that extrathyroidal NIS-expressing cancers could be targeted with 131I if NIS were present and functional.
Herein we perform an extensive survey of NIS protein expression in normal, benign, and malignant human tissue samples using conventional whole tissue sections (CWTS) and high density tissue microarrays. Our goal was to profile NIS expression across many organs and cancers using thyroid pathology as a frame of reference for judging immunoreactivity.
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Materials and Methods |
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CWTS derived from 422 thyroid and breast samples were studied and compared with tissue cores distributed in four microarrays. All samples were identified via pathological records, and archival blocks were obtained from the Departments of Pathology of Stanford University School of Medicine and Robert Wood Johnson Medical School. A total of 154 benign and malignant thyroid cases were analyzed. Adjacent morphologically normal thyroid tissue was available for evaluation in 99 instances. The remaining 169 represent normal, benign, and malignant breast samples, including 45 previously reported cases (4). All normal breast samples represent tissue sections analyzed immediately surrounding or in the vicinity of either noninvasive or invasive breast cancers. No reduction mammoplasties were included in this report. Four human tissue microarrays were each probed three times. Arrays were constructed with a tissue array instrument using 0.6-mm cores (Beecher Instruments, Silver Spring, MD). A total of 981 cores were embedded into 4 tissue microarrays, each including 5–10 placenta cores and the same repertoire of normal muscle, lymph node, tonsil, spleen, melanoma, and breast cancer cores repeated across arrays. Excluding the aforementioned cores, the composition of each array was as follows: 136 normal; 26 benign and 227 malignant breast; and 518 carcinoma divided into 2 arrays (Tables 1–5
). Some types of cancers were extensively sampled with 25 or more cores. These were: colon (n = 90), lung (n = 59), ovary (n = 47), kidney (n = 44), prostate (n = 35), uterus (n = 34), and stomach (n = 27). To supplement further the survey of normal tissues, we probed an additional 50 archival formalin-fixed, paraffin-embedded CWTS: 6 salivary gland, 1 lymph node, 2 lung, 3 prostate, 2 pancreas, 5 colon, 4 bladder, 5 endometrium, 3 myometrium, 4 placenta, 4 stomach, 3 kidney, 6 liver, 1 gallbladder, and 1 ovary. These study protocols were reviewed and approved by the institutional review board (University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School) or the administrative panel on human subjects in medical research (Stanford University School of Medicine).
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The following peptide, GHDGGRDQQETNL, corresponding to residues 631–643 of human NIS was synthesized by solid phase synthesis and used to generate a high affinity, site-directed, polyclonal Ab, as described by Levy et al. (18). Ab were affinity purified, and concentrations were approximately 1.0 µg/µl. Higher dilutions were required for immunohistochemical signal amplification procedures [catalyzed signal amplification protocol (CSA), DAKO Corp., Carpenteria, CA] because of the higher sensitivity of the system. Dilutions of NIS Ab were 1:10,000 (CSA, DAKO Corp.) and 1:400 (ENVISION Plus, DAKO Corp.). The specificity of the Ab was corroborated by the absence of immunostaining with peptide inhibition and secondary Ab only as reported previously (4).
Immunohistochemistry
Tissue microarrays and CWTS were studied using the CSA protocol (DAKO Corp.). In brief, 4-µm sections were mounted on charged slides. All sections were baked at 60 C for 30 min. Slides were washed through three changes of xylene and hydrated through alcohols to distilled water. Antigen retrieval was performed using 10% citrate buffer in a rice steamer for 40 min, and rapid cooling was achieved with distilled water. Tissues were incubated in 3% peroxide for 15 min to quench endogenous peroxidase. All washes were performed with TBST (0.3 M NaCl, 0.1% Tween 20, and 0.05 M Tris-HCl, pH 7.6) three times for 5 min each time. Sections were blocked with serum-free protein, and endogenous biotin activity was blocked with Biotin Blocking System (DAKO Corp.). Slides were incubated for 15 min with human anti-NIS Ab diluted in serum-free protein block. In selected cases immunoreactivity was competitively inhibited by the presence of 0.7 µM corresponding synthetic peptides used to generate Abs. The strepavidin-biotin method as specified by the supplier was followed (CSA kit, DAKO Corp.). Peroxidase activity was detected with diaminobenzidene-hydrogen peroxide and was observed as a brown product. A nonbiotinylated method (ENVISION Plus, DAKO Corp.) was used to further characterize NIS immunoreactivity in each tissue microarray and in some select cases. Primary anti-NIS Ab was incubated for 30 min, followed by a 15-min incubation with a labeled polymer before detection of brown product with diaminobenzidene. All slides were counterstained with toluidine blue.
Interpretation and grading
One grading system was applied to the immunohistochemical evaluation of CWTS and the microarray tissue cores. These were scored as 0 (negative), 1 (absent or uninterpretable core), 2 (weakly positive), or 3 (strongly positive). Human salivary gland sections were used as positive controls in all experiments. Diffuse, sparse immunoreactivity observed throughout core or tissue sections was considered to represent background or nonspecific staining and thus was graded negative. Immunoreactivity was characterized as either weak or strong, but had to encompass at least 20% of cells to receive this overall score. When plasma membrane immunoreactivity was noted, it was always scored as strong if 10% or more of cells demonstrated this feature either alone or in the presence of intracellular immunoreactivity. The percentage of cells demonstrating NIS positivity was not quantified beyond the criteria described above given the large sample we were profiling. The final score for each case reflects the concordance of results on multiple experiments.
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Results |
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Ninety-six carcinomas, 58 benign lesions and 99 morphologically normal (taken from tissue adjacent to the lesions) thyroid tissue sections were analyzed (Table 1
). Nearly three-quarters of normal specimens were positive for NIS, as were 3 of 4 normal thyroid cores. The distribution of NIS immunopositivity in thyroid follicular cells is exemplified in Fig. 1C. Cuboidal or column-shaped cells typically exhibited plasma membrane immunoreactivity, whereas flattened cells, encountered around distended colloid-filled follicles, demonstrated less intense and predominantly intracellular immunopositivity. Less than 30% of cells within a follicle exhibited strong plasma membrane reactivity, in accordance with previous reports (20, 21, 31, 32, 33, 34). NIS immunoreactivity was absent in some normal-appearing sections surrounding abnormal thyroid lesions. This could be attributed to the fact that only a small rim of compressed tissue was evaluated.
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, F and H). Conversely, some papillary carcinomas, particularly the follicular variant, displayed distinctive plasma membrane staining, as shown in Fig. 1G. Six cases of local-regional metastatic papillary carcinoma were analyzed. NIS expression was present in 67% of these metastases compared with 80.5% of primary papillary carcinomas. Twenty DTC were included in one of the carcinoma arrays. Three cores exhibited strong positive staining (Fig. 2H); one was negative, and the rest were weakly positive.
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Breast
Results from breast tissue cores are presented in Table 2, and results from CWTS are presented in Table 3. Altogether, they represent 371 breast samples. NIS positivity was generally higher in whole tissue sections than in cores: invasive breast carcinoma, 76% (n = 91) vs. 66% (n = 137); ductal carcinoma in situ, 88% (n = 17) vs. 68% (n = 41); fibroadenomas, 80% vs. 80%; and all normal/benign combined, excluding gestational/lactational changes, 43.5% (n = 46) vs. 27% (n = 11). The majority of normal breast cores were negative (87%), as were 70% of normal/nonproliferative (CWTS) samples analyzed. All of the latter cases were tissues surrounding or in the vicinity of carcinomas (35 invasive and 5 DCIS). Therefore, some of the samples labeled normal may correspond to tissues that have undergone biochemical changes that are not yet morphologically apparent. The 30% immunopositivity is similar to our own previous report of 23% (4). NIS was detected in 2 of 3 benign papillomas and was localized to the apical aspect of the cell, reminiscent of the intracellular distribution observed in some papillary carcinomas of the thyroid. The epithelium of fibroadenomas was immunopositive in 80% of CWTS and cores. Plasma membrane immunoreactivity was observed in gestational breast tissues (Fig. 1K), in situ ductal carcinomas (Fig. 1M), and invasive ductal carcinomas (Fig. 1, N and O).
The highly sensitive method of signal amplification was selected simply on the basis that it requires considerably less Ab. Plasma membrane immunoreactivity may be harder to discern when accompanied by strong intracellular immunopositivity, as shown in Fig. 1P. Proof of sharp plasma membrane immunoreactivity in a high grade invasive ductal carcinoma of the breast is illustrated in Fig. 1O using a less sensitive, nonbiotinylated method. The likelihood of I- transport activity is enhanced whenever NIS is immunohistochemically demonstrated in the plasma membrane. Cell membrane immunoreactivity was not observed in other normal or benign breast tissues, with the exception of gestational or lactating samples.
Tissue microarrays
Four tissue arrays containing a total of 806 evaluable cores were probed with anti-NIS Ab. Disagreement or discordant grading results among three separate tests were less than 12%. Results for breast and thyroid cores were discussed in previous sections.
Normal tissues
Thirty-four normal tissues were surveyed on a microarray containing 127 evaluable cores. Because of the limited number of samples for each organ in this array, we evaluated 50 additional whole tissue samples representing 11 tissue types to corroborate findings on tissue cores. Placental cores derived from 3 cases were interspersed repeatedly throughout the arrays and are analyzed together in this section. Less than 20% (6 of 38) of these placental cores demonstrated weak NIS immunoreactivity. However, on examination of 4 placenta cases using conventional sections, 2 were found to be negative, and another 2 exhibited distinct NIS immunoreactivity in the chorionic villi and weaker intracellular immunopositivity of cytotrophoblasts (Fig. 2A).
As expected, NIS was detected in clinically known I- transporting tissues, namely thyroid, salivary gland, and stomach. In this survey the following tissues were found to express NIS both by core and CWTS: bladder mucosa (Fig. 2F), endometrial glands (Fig. 2E), colonic mucosal cells, renal distal and collecting tubules (Fig. 1D), bronchial epithelium, intrahepatic bile canaliculi, gallbladder mucosa cells, prostate epithelium, and pancreatic exocrine cells (Fig. 2D). Immunoreactivity was particularly strong in the endometrium, bladder, kidney, and bile canaliculi. Additional tissues were found to have NIS expression in two or more microarray cores: adrenal, epididymis, and small bowel (Table 4). By comparison, parathyroid, soft tissue benign neoplasms (schwannoma, neurofibroma), cartilage, muscle, heart, nerve, skin, retina, esophagus, ovary, thymus, cervix, lung, tonsil, spleen, and lymph node did not demonstrate any immunoreactivity to anti-NIS Ab.
Carcinoma
Carcinomas arising in 25 different organs or tissue types and distributed among 2 tissue microarrays are profiled here. Of 518 cores, 479 were evaluable, including 75 colon, 58 lung, 41 kidney, and 37 ovary. NIS expression was detected in 19 carcinoma types. Although normal cervix, esophagus, lung, ovary, and skin samples were classified as negative, NIS expression was detected in 100%, 47%, 65%, 73%, and 56% of corresponding malignant cores (Table 5 and examples in Fig. 2, B and L). Endometrial, pancreatic, prostatic, and colonic carcinomas exhibited NIS immunoreactivity in 56–74% of the cores tested (Fig. 2, H, G, K, and J). One third of melanomas and 56% of squamous skin lesions showed immunoreactivity to NIS Ab also.
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Discussion |
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The NIS protein was detected in 18 of 33 extrathyroidal tissues and in 19 of 25 different carcinomas. Two hundred and fifty-three thyroid tissue sections were initially probed, and nearly 75% of them expressed NIS. Most remarkable was the prevalence of immunoreactivity in 80.5% of thyroid papillary carcinomas, which was similar to the immunopositivity noted in 19 of 20 DTC tissue cores and to published reports (31, 32).
In conventional tissue sections, the NIS protein was detected in 76% of invasive and 88% of noninvasive breast cancers, compared with 66% and 68%, respectively, in breast tissue cores. Given that heterogeneous immunoreactivity was common in breast cancers studied by CWTS, an explanation for the observed discrepancy is the possibility that subsets of tumor cells expressing NIS are more likely to be missed with one core than by conventional sections. Thus, protein expression may be underestimated when cases are evaluated with microarray technology using single cores. On the other hand, the strength of the array methodology lies in that it makes it possible to simultaneously assess large samples of cases under the same experimental conditions to determine the presence of a protein in the represented tissues. The microarray technique is a valuable screening tool that nevertheless requires further validation on standard sections.
In addition to the previously known and presently confirmed thyroid and breast carcinomas (see above), NIS was found in carcinomas involving the following organs: bladder, cervix, oropharynx, colon, lung, pancreas, prostate, skin including melanoma, stomach, ovary, and endometrium. In the vast majority of these tumors NIS was detected predominantly in the intracellular compartment. Because NIS is an integral membrane protein, intracellular distribution implies organellar localization. Normal colon epithelial cells, endometrium glandular cells, and gastric mucosa, such as thyrocytes and lactating breast cells, exhibited plasma membrane immunoreactivity. Over 50% of cancers arising in these organs also expressed NIS. Endometrial glandular cells showed evidence of distinct basolateral membrane positivity, as well as luminal intracellular localization. Weak NIS immunoreactivity was observed in 56% of endometrial carcinomas.
Our results show that NIS expression may be detectable, but weak, in many neoplastic cells, except in thyroid and breast cancer, where NIS is seemingly overexpressed, and the immunoreactivity is intense. For example, NIS expression was absent in normal lung alveolar tissue (although it was present in normal bronchial epithelium), and yet approximately two thirds of lung adenocarcinomas and squamous cell carcinomas demonstrated predominantly weak intracellular immunoreactivity. Like other investigators, we did not find NIS immunoreactivity in normal cervix, esophagus, ovary, spleen, and skin, although 46–68% of the corresponding malignant tissue cores demonstrated weak immunoreactivity (27). In all likelihood, the factors regulating NIS expression in each tissue may be quite different, as has been established for thyroid and lactating mammary gland (4, 41, 42).
Some 37.5% of bladder carcinomas showed strong NIS immunoreactivity. There have been conflicting reports regarding the localization of NIS in pancreas and salivary gland. We have observed, as have others, that islet cells and exocrine pancreatic cells are immunoreactive (22, 27). Weak acinar cell immunoreactivity could be observed in some salivary gland samples, as described by Spitzweg et al. (22), but is clearly overshadowed by the intense plasma membrane positivity of ductal cells. Disparities in the tissue-specific detection of NIS among investigators may be explained by the use of Ab directed toward different epitopes. Trophoblasts also express NIS, indicating NIS mediation of the reported transport of iodide across the placenta (29). In our experiments, NIS expression in the placenta was positive in half of the CWTS studied. The absence of NIS-positive immunohistochemical staining in the other half may be due to conditions surrounding delivery and tissue preservation factors.
It was only after the 1996 isolation of the cDNA encoding NIS and the generation of anti-NIS Abs that it became possible to assess NIS mRNA and protein expression (2, 17, 18, 19, 20, 21, 22). It has since been clearly established that NIS is the sole plasma membrane protein that mediates the active transport of I- in any tissue, healthy or cancerous, in which such transport occurs. The hallmarks of NIS function are active I- transport that is Na+ dependent and inhibitable by perchlorate. The presence of NIS protein properly targeted to the plasma membrane is required for active I- transport to take place. Therefore, the observation of active I- transport in a given tissue constitutes proof of both NIS protein expression and its proper targeting to the plasma membrane in that tissue. On the other hand, it should be emphasized that the demonstration of NIS expression in a given tissue solely by immunohistochemistry does not necessarily mean that NIS is functional in that tissue, at least in part because the expressed protein may remain in intracellular membrane compartments and not be targeted to the plasma membrane.
Indeed, regulation of the functional expression of NIS in thyroid cells is highly complex. Kogai et al. (43) have shown that TSH markedly stimulates NIS mRNA and protein levels in both monolayer and follicle-forming human primary culture thyrocytes, whereas significant stimulation of I- uptake is observed only in follicles. These interesting observations indicate that in addition to TSH stimulation, cell polarization and spatial organization are crucial for proper NIS activity in the plasma membrane and suggest that NIS may be regulated by such posttranscriptional events as subcellular distribution. Riedel et al. (44) reported that TSH regulates I- uptake in thyroid cells by modulating the subcellular distribution of NIS, without apparently influencing the intrinsic functional status of the NIS molecules. In the absence of TSH, NIS was observed intracellularly, whereas in the hormone’s presence, NIS was targeted to the plasma membrane. Hence, TSH not only stimulates NIS transcription and biosynthesis, it is also required for targeting NIS to and/or retaining it at the plasma membrane of thyrocytes.
In addition to thyroid carcinoma, radioiodide uptake has been sporadically reported in breast cancer, gastric carcinoma, ovarian cystadenoma, thymus, bronchogenic cyst, and lung carcinomas (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). The link between NIS and breast cancer is particularly significant. We have previously demonstrated that more than 80% of human breast carcinomas express NIS, and we also showed in vivo functional NIS expression in transgenic mice carrying experimental mammary tumors (4). In vivo evidence of human I- uptake activity in nonthyroid tissues comes from routine whole body 131I scintiscans performed after thyroidectomy. These studies are intended to detect residual thyroid tissue, regional and distant metastasis and are used to determine the need of radioablative therapy as well as the treatment dose (44A ).
Typically, breast tissue does not enhance on scintigraphic evaluations, a result consistent with our observations of mostly absent and sometimes weak intracellular immunoreactivity in normal nonlactating or benign breast tissue. This agrees with the established idea that NIS must be localized in the plasma membrane to mediate active I- transport. In the present study we observed no NIS expression in the majority of normal or benign breast tissue samples, and only weak intracellular immunoreactivity in a minority of samples. This suggests that even in the samples where it is expressed, NIS is not present at the plasma membrane and therefore cannot mediate active I- transport. In contrast, NIS expression is intense and present in a majority of breast carcinomas, suggesting that NIS is up-regulated during the malignant transformation of breast epithelial cells. However, the degree to which NIS may be functional in cancers with strong NIS expression remains to be determined. It is not known whether lactogenic hormones that regulate NIS expression in the lactating breast also play a role in breast malignancies or whether other as yet unidentified factors are important for NIS protein synthesis and activity in breast cancer (4).
Moon et al. (45) have reported 99mTc-pertechnetate (a widely used radioisotope also transported by NIS, with the advantage of a shorter half-life than radioiodide) accumulation in 3 of 24 breast cancer patients scintigraphically imaged. This is a highly meaningful result, not only because it demonstrates the existence of I- transport activity, but also because the observation was made in patients whose thyroids were not down-regulated (i.e. thyroid NIS activity was normal, and therefore there was avid thyroidal I- uptake). It is possible that a larger proportion of I--accumulating breast cancers may have been identified if thyroid suppression had been employed, decreasing the radioactivity in the thyroid and enhancing the detection of foci with lower uptake.
For many decades it was thought that I- transport was uniquely associated with the process of thyroid hormone iodination. Our idea of the scope of I- transporting activity may be expanding as NIS is identified in extrathyroidal tissues. As pointed out above, there is interest at NIS centers in the possibility of selectively targeting malignant lesions with 131I. Experimentally, NIS has been either transfected (melanoma, prostate, and thyroid cancer cell lines) and/or transferred with an adenoviral or retroviral vector (cervical, breast, colon, lung, prostate, and glioma cancer cell lines) to test the concept of targeted ablative therapy (5, 46, 47, 48, 49, 50, 51). Three important factors need to be considered if 131I therapy is to be used in extrathyroidal tissues: 1) degree of iodide transporting activity; 2) ability of cells to accumulate and retain radioisotope for the effective delivery of its radiation dose, even in the absence of I- organification; and 3) need to block the avid trapping of I- by the intact thyroid gland. It is certainly feasible to overcome the latter with thyroid hormone administration and antithyroid drugs that block organification of I-. Spitzweg et al. (5) established NIS-expressing human prostate cancer xenografts in nude mice and demonstrated tumor accumulation in vivo of 25–30% of administered radioiodide. Tumor volumes were dramatically reduced or became undetectable after a single ip injection of a therapeutic dose (3 mCi) of 131I (5). As pointed out above, these results provide strong evidence against the concept that iodide organification is a requirement for radioiodide therapy to be effective.
In conclusion, we have shown that tissue microarrays are a valuable technique to rapidly probe NIS expression in a wider sampling of tissues than had been attempted previously. We report that the NIS protein is expressed in many more normal tissues than previously thought and in even more malignant tissues than had been reported to date, including cancers originating in tissues that lack NIS expression. Our findings strongly suggest that NIS is not active in the overwhelming majority of normal and malignant tissues in which it is expressed, given that I- transport has only been observed in a few well described tissues. Our results suggest further that the most likely reason for the absence of I- transport activity in the majority of NIS-expressing, but non-I--transporting, tissues is the localization of NIS protein in intracellular compartments rather than at the plasma membrane. This underscores the need to identify the regulatory mechanisms that govern NIS expression and targeting to the plasma membrane in both normal and cancerous extrathyroidal tissues, with the goal of developing strategies to render NIS active for the possible use of radioiodide as an anticancer treatment in a wide variety of tumors. This would enable us to greatly expand the reach of one of the most effective and least toxic targeted internal radiation anticancer therapies available, which has been successfully used for more than 60 yr in the treatment of thyroid cancer.
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Acknowledgments |
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Footnotes |
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Abbreviations: Ab, Antibody; CSA, catalyzed signal amplification protocol; CWTS, conventional whole tissue sections; DTC, differentiated thyroid cancer; NIS, Na+/I- symporter.
Received October 3, 2002.
Accepted January 15, 2003.
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J. Faivre, J. Clerc, R. Gerolami, J. Herve, M. Longuet, B. Liu, J. Roux, F. Moal, M. Perricaudet, and C. Brechot Long-Term Radioiodine Retention and Regression of Liver Cancer after Sodium Iodide Symporter Gene Transfer in Wistar Rats Cancer Res., November 1, 2004; 64(21): 8045 - 8051. [Abstract] [Full Text] [PDF]
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K. A. B. Knostman, J.-Y. Cho, K.-Y. Ryu, X. Lin, J. A. McCubrey, T. Hla, C. H. Liu, E. Di Carlo, R. Keri, M. Zhang, et al. Signaling through 3',5'-Cyclic Adenosine Monophosphate and Phosphoinositide-3 Kinase Induces Sodium/Iodide Symporter Expression in Breast Cancer J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5196 - 5203. [Abstract] [Full Text] [PDF]
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 I. L. Wapnir, M. Goris, A. Yudd, O. Dohan, D. Adelman, K. Nowels, and N. Carrasco The Na+/I- Symporter Mediates Iodide Uptake in Breast Cancer Metastases and Can Be Selectively Down-Regulated in the Thyroid Clin. Cancer Res., July 1, 2004; 10(13): 4294 - 4302. [Abstract] [Full Text] [PDF]
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 L. S. Zuckier, O. Dohan, Y. Li, C. J. Chang, N. Carrasco, and E. Dadachova Kinetics of Perrhenate Uptake and Comparative Biodistribution of Perrhenate, Pertechnetate, and Iodide by NaI Symporter-Expressing Tissues In Vivo J. Nucl. Med., March 1, 2004; 45(3): 500 - 507. [Abstract] [Full Text]
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T. Kogai, Y. Kanamoto, L. H. Che, K. Taki, F. Moatamed, J. J. Schultz, and G. A. Brent Systemic Retinoic Acid Treatment Induces Sodium/Iodide Symporter Expression and Radioiodide Uptake in Mouse Breast Cancer Models Cancer Res., January 1, 2004; 64(1): 415 - 422. [Abstract] [Full Text] [PDF]
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A.-C. Gerard, C. Daumerie, C. Mestdagh, S. Gohy, C. de Burbure, S. Costagliola, F. Miot, M.-C. Nollevaux, J.-F. Denef, J. Rahier, et al. Correlation between the Loss of Thyroglobulin Iodination and the Expression of Thyroid-Specific Proteins Involved in Iodine Metabolism in Thyroid Carcinomas J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4977 - 4983. [Abstract] [Full Text] [PDF]
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