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Endogenous NIS Expression in Triple-Negative Breast Cancers

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The sodium iodide symporter (NIS) mediates iodide transport into cells and has been identified in approximately 70% of breast cancers. Functional NIS expression raises the possibility of using 131I for therapeutic targeting of tumor cells. Treatment of triple-negative breast cancers [estrogen/progesterone receptor-negative and HER2-negative (ER−/PR−/HER2−)] is primarily limited to chemotherapy. Our aim was to characterize NIS expression in this subset of tumors.

Methods

Archival tissue sections from 23 women with triple-negative breast cancer were analyzed for NIS expression using immunohistochemical methods and an anti-human NIS antibody. Tumors were evaluated for the presence of plasma membrane immunoreactivity. One patient with a NIS-expressing positive tumor underwent 123I scintigraphic imaging with dosimetric analysis.

Results

Fifteen cases (65.2%) demonstrated NIS-positivity with 11 tumors (47.8%) exhibiting strong expression. Plasma membrane immunoreactivity was observed in four breast cancers and was equivocal in another four tumors. Tumor-specific radioiodide uptake was demonstrated by 123I scintigraphy in a patient with a large primary breast cancer unresponsive to neoadjuvant therapy. The tumor concentrated 2.05, 1.53, and 1.96 times more isotope than normal breast tissue at 1, 5, and 21 h. The relative increased uptake is consistent with positive NIS expression in the tumor on definitive surgery; however, the cumulative concentration in the tumor was not sufficient to achieve a therapeutic effect, had the isotope been 131I.

Conclusions

NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells, suggesting a potential role for NIS-directed 131I-radioablative strategies in this patient population.

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References

  1. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418–23.

    Article  PubMed  CAS  Google Scholar 

  2. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol. 2005;3:7350–60.

    Article  PubMed  CAS  Google Scholar 

  3. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–34.

    Article  PubMed  CAS  Google Scholar 

  4. Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007;8:235–44.

    Article  PubMed  Google Scholar 

  5. Kreike B, van de Vijver MJ. Are triple-negative tumours and basal-like breast cancer synonymous? Authors’ response. Breast Cancer Res. 2007;9:405.

    Article  Google Scholar 

  6. Rakha EA, Tan DS, Foulkes WD, Ellis IO, Tutt A, Nielsen TO. Are triple negative tumours and basal-like breast cancer synonymous? Breast Cancer Res. 2007;9:R80.

    Article  Google Scholar 

  7. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502.

    Article  PubMed  CAS  Google Scholar 

  8. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–34.

    Article  PubMed  Google Scholar 

  9. van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi O, Kononen J, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol. 2002;161:1991–6.

    PubMed  Google Scholar 

  10. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.

    Article  PubMed  CAS  Google Scholar 

  11. Arnes JB, Brunet JS, Stefansson I, Begin LR, Wong N, Chappuis PO, et al. Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res. 2005;11:4003–11.

    Article  PubMed  CAS  Google Scholar 

  12. Rodriguez-Pinilla SM, Sarrio D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res. 2006;12:1533–9.

    Article  PubMed  CAS  Google Scholar 

  13. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer. 2007;109:25–32.

    Article  PubMed  CAS  Google Scholar 

  14. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24:5652–7.

    Article  PubMed  Google Scholar 

  15. Carlson RW AC, Anderson BO, et al. NCCN Clinical Practice Guidelines in Oncology-Breast Cancer. National Comprehensive Cancer Network 2008, vol. 2; NCCN, Fort Washington, PA; 2008.

  16. Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med. 2000;6:871–8.

    Article  PubMed  CAS  Google Scholar 

  17. Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K, et al. Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab. 2003;88:1880–8.

    Article  PubMed  CAS  Google Scholar 

  18. Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature. 1996;379:458–60.

    Article  PubMed  CAS  Google Scholar 

  19. Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, et al. Cloning of the human sodium lodide symporter. Biochem Biophys Res Commun. 1996;226:339–45.

    Article  PubMed  CAS  Google Scholar 

  20. Caillou B, Troalen F, Baudin E, Talbot M, Filetti S, Schlumberger M, et al. Na+/I−symporter distribution in human thyroid tissues: an immunohistochemical study. J Clin Endocrinol Metab. 1998;83:4102–6.

    Article  PubMed  CAS  Google Scholar 

  21. Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, et al. Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells. Endocrinology. 2005;146:3059–69.

    Article  PubMed  CAS  Google Scholar 

  22. Dohan O, Baloch Z, Banrevi Z, Livolsi V, Carrasco N: Rapid communication: predominant intracellular overexpression of the Na(+)/I(–) symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab. 2001;86:2697–700.

    Article  PubMed  CAS  Google Scholar 

  23. Schlumberger M, Tubiana M, De Vathaire F, Hill C, Gardet P, Travagli JP, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab. 1986;63:960–7.

    PubMed  CAS  Google Scholar 

  24. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab. 1985;60:376–80.

    Article  PubMed  CAS  Google Scholar 

  25. Moon DH, Lee SJ, Park KY, Park KK, Ahn SH, Pai MS, et al. Correlation between 99mTc-pertechnetate uptakes and expressions of human sodium iodide symporter gene in breast tumor tissues. Nucl Med Biol. 2001;28:829–34.

    Article  PubMed  CAS  Google Scholar 

  26. Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, et al. The Na+/I−symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid. Clin Cancer Res. 2004;10:4294–302.

    Article  PubMed  CAS  Google Scholar 

  27. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40:37S–61S.

    PubMed  CAS  Google Scholar 

  28. Maxon HR, Thomas SR, Boehringer A, Drilling J, Sperling MI, Sparks JC, et al. Low iodine diet in I-131 ablation of thyroid remnants. Clin Nucl Med. 1983;8:123–6.

    Article  PubMed  CAS  Google Scholar 

  29. Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z. Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther. 2003;2:1113–20.

    PubMed  CAS  Google Scholar 

  30. Bruno R, Giannasio P, Ronga G, Baudin E, Travagli JP, Russo D, et al. Sodium iodide symporter expression and radioiodine distribution in extrathyroidal tissues. J Endocrinol Invest. 2004;27:1010–4.

    PubMed  CAS  Google Scholar 

  31. Dohan O, Carrasco N. Advances in Na(+)/I(−) symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol. 2003;213:59–70.

    Article  PubMed  CAS  Google Scholar 

  32. Unterholzner S, Willhauck MJ, Cengic N, Schutz M, Goke B, Morris JC, et al. Dexamethasone stimulation of retinoic acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells. J Clin Endocrinol Metab. 2006;91:69–78.

    Article  PubMed  CAS  Google Scholar 

  33. Dohan O, De la Vieja A, Carrasco N. Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in breast cancer cells. Mol Endocrinol. 2006;20:1121–37.

    Article  PubMed  CAS  Google Scholar 

  34. Knostman KA, McCubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM. PI3 K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer. 2007;7:137.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Irene Wapnir MD.

Additional information

Kent Nowles—Posthumous.

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Renier, C., Yao, C., Goris, M. et al. Endogenous NIS Expression in Triple-Negative Breast Cancers. Ann Surg Oncol 16, 962–968 (2009). https://doi.org/10.1245/s10434-008-0280-9

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  • DOI: https://doi.org/10.1245/s10434-008-0280-9

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