Abstract
Breast cancer brain metastases are on the rise and their treatment is hampered by the limited entry and efficacy of anticancer drugs in this sanctuary. The sodium iodide symporter, NIS, actively transports iodide across the plasma membrane and is exploited clinically to deliver radioactive iodide into cells. As in thyroid cancers, NIS is expressed in many breast cancers including primary and metastatic tumors. In this study NIS expression was analyzed for the first time in 28 cases of breast cancer brain metastases using a polyclonal anti-NIS antibody directed against the terminal C-peptide of human NIS gene and immunohistochemical methods. Twenty-five tumors (84%) in this retrospective series were estrogen/progesterone receptor-negative and 15 (53.6%) were HER2+. Overall 21 (75%) cases and 80% of HER2 positive metastases were NIS positive. While the predominant pattern of NIS immunoreactivity is intracellular, plasma membrane immunopositivity was detected at least focally in 23.8% of NIS-positive samples. Altogether, these findings indicate that NIS expression is prevalent in breast cancer brain metastases and could have a therapeutic role via the delivery of radioactive iodide and selective ablation of tumor cells.
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Lee YT (1983) Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 23:175–180
Pelletier EM, Shim B, Goodman S, Amonkar MM (2008) Epidemiology and economic burden of brain metastases among patients with primary breast cancer: results from a US claims data analysis. Breast Cancer Res Treat 108:297–305
Crivellari D, Pagani O, Veronesi A, Lombardi D, Nole F, Thurlimann B, Hess D, Borner M, Bauer J, Martinelli G, Graffeo R, Sessa C, Goldhirsch A (2001) High incidence of central nervous system involvement in patients with metastatic or locallyadvanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 12:353–356
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit cancer surveillance system. J Clin Oncol 22:2865–2872. doi:10.1200/JCO.2004.12.149
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684
Lee SS, Ahn JH, Kim MK, Sym SJ, Gong G, Ahn SD, Kim SB, Kim WK (2008) Brain metastases in breast cancer: prognostic factors and management. Breast Cancer Res Treat 111:523–530
Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R, Winer E (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97:2972–2977
Shmueli E, Wigler N, Inbar M (2004) Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. Eur J Cancer 40:379–382
Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B (2006) Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24:5658–5663. doi:10.1200/JCO.2006.07.0250
Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13:1648–1655. doi:10.1158/1078-0432.CCR-06-2478
Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP (2009) Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 15:1452–1459
Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379:458–460
Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG, Carrasco N (2000) The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med 6:871–878
Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM (1996) Cloning of the human sodium lodide symporter. Biochem Biophys Res Commun 226:339–345
Spitzweg C, Dietz AB, O’Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC (2001) In vivo sodium iodide symporter gene therapy of prostate cancer. Gene Ther 8:1524–1531
Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K, Greco RS, Dohan O, Carrasco N (2003) 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 88:1880–1888
Schlumberger M, Tubiana M, De Vathaire F, Hill C, Gardet P, Travagli JP, Fragu P, Lumbroso J, Caillou B, Parmentier C (1986) Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 63:960–967
Samaan NA, Schultz PN, Haynie TP, Ordonez NG (1985) Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab 60:376–380
Mazzaferri E (1996) Radioiodine and other treatment and outcomes. In: RD Blau (ed) Werner and Ingbar’s the thyroid: a fundamental and clinical text. JB Lipincott, Philadelphia, pp 904–929
Renier C, Yao C, Goris M, Ghosh M, Nowles K, Gambhir SS, Wapnir I (2009) Endogenous NIS expression in triple negative breast cancers. Ann Surg Oncol 16:962–968
Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, Carrasco N (2004) The Na+/I− symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid. Clin Cancer Res 10:4294–4302
Mandell RB, Mandell LZ, Link CJ Jr (1999) Radioisotope concentrator gene therapy using the sodium/iodide symporter gene. Cancer Res 59:661–668
Kogai T, Kanamoto Y, Che LH, Taki K, Moatamed F, Schultz JJ, Brent GA (2004) Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse breast cancer models. Cancer Res 64:415–422
Ghosh M, Gambhir SS, De A, Nowels K, Goris M, Wapnir I (2006) Bioluminescent monitoring of NIS-mediated (131)I ablative effects in MCF-7 xenografts. Mol Imaging 5:76–84
Kogai T, Taki K, Brent GA (2006) Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer 13:797–826
Palmieri D, Bronder JL, Herring JM, Yoneda T, Weil RJ, Stark AM, Kurek R, Vega-Valle E, Feigenbaum L, Halverson D, Vortmeyer AO, Steinberg SM, Aldape K, Steeg PS (2007) Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res 67:4190–4198
Lin NU, Bellon JR, Winer EP (2004) CNS metastases in breast cancer. J Clin Oncol 22:3608–3617
Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT, Tubbs RR, Casey G, Weil RJ (2006) Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 30:1097–1104
Viani GA, Castilho MS, Salvajoli JV, Pellizzon AC, Novaes PE, Guimaraes FS, Conte MA, Fogaroli RC (2007) Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems. BMC Cancer 7:53
Wen PY, Loeffler JS (2000) Brain metastases. Curr Treat Options Oncol 1:447–458
Kusuhara H, Sugiyama Y (2005) Active efflux across the blood-brain barrier: role of the solute carrier family. NeuroRx 2:73–85
Girardin F (2006) Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin Neurosci 8:311–321
Boogerd W, Vos VW, Hart AA, Baris G (1993) Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol 15:165–174
Chiu AC, Delpassand ES, Sherman SI (1997) Prognosis and treatment of brain metastases in thyroid carcinoma. J Clin Endocrinol Metab 82:3637–3642
Salvati M, Frati A, Rocchi G, Masciangelo R, Antonaci A, Gagliardi FM, Delfini R (2001) Single brain metastasis from thyroid cancer: report of twelve cases and review of the literature. J Neurooncol 51:33–40
Datz FL (1986) Cerebral edema following iodine-131 therapy for thyroid carcinoma metastatic to the brain. J Nucl Med 27:637–640
Schlumberger MJ (1998) Papillary and follicular thyroid carcinoma. N Engl J Med 338:297–306
Riedel C, Levy O, Carrasco N (2001) Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin. J Biol Chem 276:21458–21463
Unterholzner S, Willhauck MJ, Cengic N, Schutz M, Goke B, Morris JC, Spitzweg C (2006) Dexamethasone stimulation of retinoic Acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells. J Clin Endocrinol Metab 91:69–78
Knostman KA, McCubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM (2007) PI3 K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer 7:137
Ohashi E, Kogai T, Kagechika H, Brent GA (2009) Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells. Cancer Res 69:3443–3450
Cho JY, Shen DH, Yang W, Williams B, Buckwalter TL, La Perle KM, Hinkle G, Pozderac R, Kloos R, Nagaraja HN, Barth RF, Jhiang SM (2002) In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas. Gene Ther 9:1139–1145
Sgouros G, Kolbert KS, Sheikh A, Pentlow KS, Mun EF, Barth A, Robbins RJ, Larson SM (2004) Patient-specific dosimetry for 131I thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software. J Nucl Med 45:1366–1372
Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24:48–77
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Renier, C., Vogel, H., Offor, O. et al. Breast cancer brain metastases express the sodium iodide symporter. J Neurooncol 96, 331–336 (2010). https://doi.org/10.1007/s11060-009-9971-8
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DOI: https://doi.org/10.1007/s11060-009-9971-8