Skip to main content

Advertisement

SpringerLink
Log in

Analysis Natrium Iodide Symporter Expression in Breast Cancer Subtypes for Radioiodine Therapy Response

  • Original Article
  • Published:
Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

This study investigates natrium iodide symporter (NIS) expression in three breast cancer subtypes to predict radioiodine response.

Materials and Methods

Frozen breast tissues from triple negative (TN), human epidermal receptor 2 (HER2+), and luminal A cancers were used in this research. NIS protein expression in each subtype was analyzed using immunohistochemistry (IHC) and western blot (WB). Secondary data such as age, subtypes, and Ki 67 index were drawn from the surgical oncologist database. Breast cancer cell lines were used to investigate the effect of radioiodine by measuring cell proliferation.

Results

The forty-one breast cancer samples were analyzed consisted of the following subtypes: TN, HER2+, and luminal A were 58%, 22%, and 20% respectively. The stages of disease were 2A to 4A. Most of samples were at 3B. Ki 67 index of TN, HER2+, and luminal A were 21 ± 12, 19 ± 5, and 7 ± 3 respectively. The NIS expression was detected in 95% of samples in cytoplasm and/or cell membrane; 93% of samples were invasive breast carcinomas. Only 20% of the samples showed NIS expression at cell membrane; four samples were HER2+, and other four were TN subtypes. NIS membrane score was significantly positively correlated with Ki67 index, p = 0.04. NIS protein expression was detected at sizes 88 kDa, 50 kDa, and 27 kDa. Cell proliferation rate means of MDA-MB 231, SKBR3, and MCF7 cells were 81.6 ± 4, 10.6 ± 5, and 15.4 ± 13 respectively (p = 0.009).

Conclusion

NIS protein expression is detectable in breast cancer cells to varying degrees. HER2+ is the most likely to express NIS in the cell membrane followed by TN subtypes. This indicates that radioiodine could be used as a novel adjuvant treatment in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ng CH, Bhoo Pathy N, Taib NA, et al. Comparison of breast cancer in Indonesia and Malaysia - a clinico-pathological study between Dharmais Cancer Centre Jakarta and University Malaya Medical Centre, Kuala Lumpur. Asian Pac J Cancer Prev. 2011;12:2943–6.

    PubMed  CAS  Google Scholar 

  2. Leong SP, Shen Z, Liu T, Agarwal G, Tajima T, Paik N, et al. Is breast cancer the same disease in Asian and Western countries? World J Surg. 2010;34:3208–24.

    Article  Google Scholar 

  3. Perry CS, Otero JC, Palmer JL, Gross AS. Risk factors for breast cancer in east Asian women relative to women in the west. Asia Pac J Clin Oncol. 2009;5:219–31.

    Article  Google Scholar 

  4. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, et al. Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res. 2015;5:2929–43.

    PubMed  PubMed Central  CAS  Google Scholar 

  5. Micali S, Bulotta S, Puppin C, Territo A, Navarra M, et al. Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer. BMC Cancer. 2014;14:303.

    Article  CAS  Google Scholar 

  6. De La Vieja A, Dohan O, Levy O, Carrasco N. Molecular analysis of the sodium/iodide symporter: impact on thyroid and extrathyroid pathophysiology. Physiol Rev. 2000;80:1083–105.

    Article  Google Scholar 

  7. Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther. 2012;135:355–70.

    Article  CAS  Google Scholar 

  8. Abdel-Hafiz HA. Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Disease. 2017;5:16.

    Article  CAS  Google Scholar 

  9. Hultsch S, Kankainen M, Paavolainen L, Kovanen R, Ikonen E, Kangaspeska S, et al. Association of tamoxifen resistance and lipid reprogramming in breast cancer. BMC Cancer. 2018;18:850.

    Article  CAS  Google Scholar 

  10. Zhang W, Ding W, Chen Y, Feng Y, Ouyang Y, Yu Y, et al. Up-regulation of breast cancer resistance protein plays a role in HER-2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells. Acta Biochim Biophys Sin. 2011;43:647–53.

    Article  CAS  Google Scholar 

  11. O’Reilly EA, Gubbins L, Sharma S, Tully R, Guang MHZ, Weiner-Gorzel K, et al. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin. 2015;3:257–75.

    Article  Google Scholar 

  12. Darrouzet E, Lindenthal S, Marcellin D, Pellequer JL, Pourcher T. The sodium/iodide symporter: state of art of its molecular characterization. Biochim Biophys Acta. 1838;2013:244–53.

    Google Scholar 

  13. Tazebay UH. Regulation of the functional Na+/I- symporter (NIS) expression in breast cancer cells. In: Done S. editor. Breast cancer - recent advances in biology, imaging and therapeutics. In Tech; 2011; p. 103–122.

  14. Bizhanova A, Koop P. The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology. 2009;150:1084–90.

    Article  CAS  Google Scholar 

  15. Kelkar MG, Senthilkumar K, Jadhav S, Gupta S, Ahn BC, De A. Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation. Sci Rep. 2016;6:19341.

    Article  CAS  Google Scholar 

  16. Oh JR, Ahn BC. False positive uptake on radioiodine whole body scintigraphy physiologic and pathologic variants unrelated to thyroid cancer. Am J Nucl Med Mol Imaging. 2012;2:362–85.

    PubMed  PubMed Central  Google Scholar 

  17. Liu Z, Xing M. Induction of sodium/iodide symporter (NIS) expression and radioiodine uptake in non-thyroid cancer cells. PLoS One. 2012;7:e31729.

    Article  CAS  Google Scholar 

  18. Beyer SJ, Jimenez RE, Shapiro CL, Cho JY, Jhiang SM. Do cell surface trafficking impairments account for variable cell surface sodium iodide symporter level in breast cancer? Breast Cancer Res Treat. 2009;115:205–12.

    Article  CAS  Google Scholar 

  19. Reiner C, Yao C, Goris M, Ghosh M, Katznelson L, Nowles K, et al. Expression in triple-negative breast cancers. Ann Surg Oncol. 2009;16:962–8.

    Article  Google Scholar 

  20. 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  CAS  Google Scholar 

  21. Wapnir IL, Van de Rijn M, Nowels K, Walton K, Montgomery K, Greco RS, 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  CAS  Google Scholar 

  22. Beyer SJ, Zhang X, Jimenez RE, Lee ML, Richard AL, et al. Microarrays analysis of genes associated with cell surface NIS protein levels in breast cancer. BMC Res Notes. 2011;4:397.

    Article  CAS  Google Scholar 

  23. Bustreo S, Osella-Abate S, Cassoni P, Donadio M, Airoldi M, Pedani F, et al. Optimal Ki67 cut-off for luminal breast Cancer prognostic evaluation: a large case series study with long-term follow-up. Breast Cancer Res Treat. 2016;157:363–71.

    Article  CAS  Google Scholar 

  24. Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013;31:3397–4013.

    Article  Google Scholar 

  25. Arroyo-Helguera O, Anguiono B, Delgado G, Aceves C. Uptake and antiproliferative effect of molecular iodine in MCF7 breast cancer cell line. Endocr Relat Cancer. 2006;13:1147–58.

    Article  CAS  Google Scholar 

  26. Knostman KA, Mc Cubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM. PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer. 2007;25:137.

    Article  CAS  Google Scholar 

  27. Hingorani M, Spitzweg C, Vassaux G, Newbold K, Melcher A, Pandha H, et al. The biology the sodium iodide symporter and its potential for targeted gene delivery. Curr Cancer Drug Targets. 2010;10:242–67.

    Article  CAS  Google Scholar 

  28. Jhiang SM, Cho JY, Ryu KY, De Young BR, Smanik PA, McGaughy VR, et al. An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology. 1998;139:4416–9.

    Article  CAS  Google Scholar 

  29. Peyrottes I, Navarro V, Ondo-Mendez A, Marcellin D, Bellanger L, Marsault R, et al. Immunoanalysis indicates that the sodium iodide symporter is not overexpressed in intracellular compartments in thyroid and breast cancers. Eur J Endocrinol. 2009;160:215–25.

    Article  CAS  Google Scholar 

  30. Chung T, Youn H, Yeom CJ, Kang KW, Chung JK. Glycosylation of sodium/iodide symporter (NIS) regulates its membrane translocation and radioiodine uptake. PLoS One. 2015;10:1–14.

    Google Scholar 

  31. Elliyanti A, Putra AE, Sribudiani Y, Noormartany N, Masjhur JS, et al. Epidermal growth factor and adenosine triphosphate induce natrium iodide symporter expression in breast cancer cell lines. Open Access Maced J Med Sci. 2019;7:1–5.

    Article  Google Scholar 

  32. 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  CAS  Google Scholar 

  33. Martins de Morais R, Sobrinho AB, Maria de Souza Silva C, Reis de Oliveira J, da Silva Izabel Cristina R. The role of the NIS (SLC5A5) gene in papillary thyroid cancer: a systematic review. Int J Endocrinol. 2018:1–11.

    Article  CAS  Google Scholar 

  34. Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC. The sodium iodide symporter and its potential role in cancer therapy. J Clin Endocrinol Metab. 2001;86:3327–35.

    Article  CAS  Google Scholar 

  35. Castro MR, Bergert ER, Goellner JR, Hay ID, Morris JC. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake. J Clin Endocrinol Metab. 2001;86:5627–32.

    Article  CAS  Google Scholar 

  36. Riesco-Eizaguirre G, Santisteban PA. Perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 2006;155:495–512.

    Article  CAS  Google Scholar 

  37. Elliyanti A, Susilo VY, Setiyowati S, Ramli M, Masjhur JS, Achmad TH. Uptake and cytotoxicity characterization of radioiodine in MCF-7 and SKBR3 breast cancer cell lines. Atom Indones. 2016;42:145–9.

    Article  Google Scholar 

  38. 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;5:1121–37.

    Article  CAS  Google Scholar 

  39. Yahyapour R, Motevaseli E, Rezaeyan A, Abdollahi H, Farhood B, Cheki M, et al. Mechanisms of radiation bystander and non-targeted effects: implications to radiation carcinogenesis and radiotherapy. Curr Radiopharm. 2018;11:1–12.

    Article  CAS  Google Scholar 

  40. Najafi M, Fardid R, Hadadi GH, Fardid M. The mechanisms of radiation- induced bystander effect. J Biomed Phys Eng. 2014;4:163–72.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Marín A, Martín M, Liñán O, Alvarenga F, López M, Fernández L, et al. Bystander effects and radiotherapy. Rep Pract Oncol Radiother. 2014;20:12–21.

    Article  Google Scholar 

Download references

Acknowledgements

Thanks are expressed to the following:

1. The Society of Oncology Surgeon of Indonesia, Padang (Peraboi-Padang), for providing the secondary data

2. Faculty of Medicine, Universitas Padjadjaran, Indonesia; Dr. Ahmad Faried MD gifted MCF7 cell lines and Dr.med. Muhammad Hasan Bashari MD gifted MD-MB 231 cell line

3. The Center of Radioisotope and Radiopharmaceutical Technology, Badan Tenaga Nuklir Nasional for facilitate the research collaboration

4. Mrs. Fay Farley for English manuscript preparation of this paper

Funding

The Faculty of Medicine Universitas Andalas, Indonesia, provided the grant for this study (contract number 96/BBPT/PNP-FK-Unand-2016).

Author information

Authors and Affiliations

  1. Medical Physics and Radiology Departments, Faculty of Medicine, Universitas Andalas, Kampus Limau Manis, Padang, West Sumatera, 25163, Indonesia

    Aisyah Elliyanti

  2. Anatomy Department, Faculty of Medicine, Universitas Andalas, Padang, Indonesia

    Dewi Rusnita

  3. Histology Department, Faculty of Medicine, Universitas Andalas, Padang, Indonesia

    Nita Afriani

  4. Pathology Anatomy Department, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Yayi Dwina Billianti Susanto

  5. The Center of Radioisotopes and Radiopharmaceuticals Technology, Badan Tenaga Nuklir Nasional, Puspitek Serpong, Tangerang Selatan, Indonesia

    Veronica Y. Susilo & Sri Setiyowati

  6. Surgery Department, Faculty of Medicine, Universitas Andalas, Padang, Indonesia

    Wirsma Arif Harahap

Authors
  1. Aisyah Elliyanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dewi Rusnita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nita Afriani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yayi Dwina Billianti Susanto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veronica Y. Susilo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sri Setiyowati
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wirsma Arif Harahap
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aisyah Elliyanti.

Ethics declarations

Conflict of Interest

Aisyah Elliyanti, Dewi Rusnita, Nita Afriani, Yayi Dwina Billianti Susanto, Veronica Y Susilo, Sri Setiyowati, and Wirsma Arif Harahap declare no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

The institutional review board of our institute approved this study and the requirements to obtain informed consent were waived.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elliyanti, A., Rusnita, D., Afriani, N. et al. Analysis Natrium Iodide Symporter Expression in Breast Cancer Subtypes for Radioiodine Therapy Response. Nucl Med Mol Imaging 54, 35–42 (2020). https://doi.org/10.1007/s13139-019-00632-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13139-019-00632-8

Keywords

Search

Navigation