V L POOLE and C J MCCABE Iodide transport and breast 227:1 R1–R12 Review cancer Iodide transport and breast cancer Correspondence Vikki L Poole and Christopher J McCabe should be addressed to C J McCabe School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Email Birmingham B15 2TT, UK [email protected] Abstract Breast cancer is the second most common cancer worldwide and the leading cause of cancer Key Words death in women, with incidence rates that continue to rise. The heterogeneity of the disease " breast cancer makes breast cancer exceptionally difficult to treat, particularly for those patients with " iodide transport triple-negative disease. To address the therapeutic complexity of these tumours, new " radioiodide strategies for diagnosis and treatment are urgently required. The ability of lactating and " sodium iodide malignant breast cells to uptake and transport iodide has led to the hypothesis that symporter (NIS) radioiodide therapy could be a potentially viable treatment for many breast cancer patients. " pendrin Understanding how iodide is transported, and the factors regulating the expression and " sodium-coupled monocarboxylate function of the proteins responsible for iodide transport, is critical for translating this transporter (SMCT) hypothesis into reality. This review covers the three known iodide transporters – the sodium iodide symporter, pendrin and the sodium-coupled monocarboxylate transporter – and their role in iodide transport in breast cells, along with efforts to manipulate them to increase the potential for radioiodide therapy as a treatment for breast cancer. Journal of Endocrinology (2015) 227, R1–R12 Journal of Endocrinology Introduction Based on current incidence projections, 3.2 million new how they may be manipulated is required for this proposed cases of breast cancer will be diagnosed each year by 2050 treatment to become a reality. This review aims to provide (Hortobagyi et al.2005). Meanwhile, the heterogeneity an overview of the transporters sodium iodide symporter observed at both the intra- and inter-tumour levels (NIS), pendrin and sodium-coupled monocarboxylate continues to make the disease challenging to treat, transporter (SMCT), focusing on factors relating to their particularly for those patients with metastatic triple- expression and function alongside strategies that would negative disease, where few treatment options are available. maximise their potential in breast cancer. The inherent ability of breast cells to uptake iodide opens the possibility for a potential alternative treatment for breast Sodium iodide symporter cancer via radioiodide therapy, currently used in the management and diagnostic imaging of thyroid disorders. The NIS is a large (643 amino acids) integral plasma Although utilisation of radioiodide treatment for membrane glycoprotein (Fig. 1), the primary role of which K breast cancer has been proposed previously, improved is transporting iodide (I ) into cells. The gene, also functional insight is required before it can be translated referred to as solute carrier family 5 member 5 (SLC5A5), from bench to bedside. Crucially, the transport of iodide was first cloned in 1996 (Dai et al. 1996), although the into breast cells must be maximal while iodide efflux is ability of the thyroid to accumulate iodide was reported simultaneously minimised. Full functional understanding as early as 1896 (Baumann 1896). The protein consists of the three major transporters of iodide in breast cells and of thirteen transmembrane domains, an extracellular http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-15-0234 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 07:32:29PM via free access Review V L POOLE and C J MCCABE Iodide transport and breast 227:1 R2 cancer N-terminal and a cytosolic C-terminal tail and has been TSH receptor (TSHR), adenylate cyclase is activated, identified to be phosphorylated in vivo and contain three leading to increased intracellular cAMP levels (Takasu N-linked glycosylation sites at positions 225, 485 and 497 et al. 1978), which further activates the transcription (Fig. 1)(Levy et al. 1998, Vadysirisack et al. 2007). factors, cAMP response element-binding protein (CREB) NIS expression is primarily observed in the thyroid and Pax8 (Poleev et al. 1997). The NIS upstream enhancer along with salivary glands, gastric mucosa and lactating (NUE), which is fundamental in the initiation of NIS mammary gland cells, where it is usually located at the transcription, contains binding sites for both Pax8 and basolateral surface of the plasma membrane. In thyroid CREB, which stimulate NIS transcription upon trans- follicular cells, the cellular concentration of iodide is cription factor binding (Ohno et al. 1999). 20–50 times that of extracellular levels, so use of the inverse Only two putative binding partners of NIS have been C C C Na electrochemical gradient, maintained by the Na /K reported, both of which have been implicated with breast ATPase, allows NIS to couple the transport of one iodide cancer; pituitary tumour transforming gene (PTTG) anion and two sodium cations into cells. The NIS- binding factor (PBF) (Smith et al. 2009) and leukaemia- K mediated transport of I into thyroid follicular cells is associated RhoA guanine exchange factor (LARG) (Lacoste the first and rate-limiting step of the biosynthesis of the et al. 2012). PBF is a small glycoprotein that shares no thyroid hormones triiodothyronine (T3) and throxyine significant homology to other human proteins but is (T4)(Spitzweg et al. 2001). In the thyroid, the expression of widely conserved through a large range of species (Chien NIS is principally regulated by the thyroid-stimulating & Pei 2000). The upregulation of PBF has been reported in hormone (TSH) (Kogai et al. 1997). When TSH binds to the a number of carcinomas, including thyroid, breast and S G P A N D L L D P A L A L S N S R V A S P S Extracellular L A S V G L A C R A V L T Q A M S Q N S D H R P A S V L E P R G R I S T S R V G I L M R G G N L A A Y R M D L T P E E A Y V P Journal of Endocrinology F L Q A M R E G L N D P P E L P S L M Q D D S A T P K V P Y D T R C P S G F V F V G G M A 88 L 163 S D 308 413 Q G P F Y 525 W 16 G 75 L 158 Q D 208 R T P 326 L S 416 Y 466 A D R 241 Y V L W N I A Y Y L V F L I Q M I L W L F G T S Y L G C A T F W L V L T V M F V V A S L S L W V V M F V L G G L G A Y A M L G Q A P A L F T V D L G A Y Y F I V G L M L S F L G T S G S L V I G C F S S L I V W L L A L V I M V C A S A S N I I G E S L G T V V G I C T V V V G T S A A D L P T V A G P L L A L S L S G S L G L L T V V L T T Y L F Q S L G T T M T Y F V L W V V I G P V C A F A G A G V G I G L P F A A D S L L S I L L A A M L V A T L C G L I V G G T M Y G F F L A G I G M G A V W L P W V V G L C I Y F L A L G V Y M L R F V N V A L L V I A L Q 136 185 K 547 38R R 53 R Y 110 A 186 Q 263 Q 286 S Y 348 S 438 P G 444 S S T T G 391 C R L G G L G A N T L A T P L A C G K P G G G Q I L C N T G P T L K G Q T L V R V L S L L S W R F T A Q L T W I S A F S R R A A D E D S I T Y L S Y F T V L E V K S R I L A Y A A M N K R L E C Q N T Q A R E R K M P T T A P D L E A Intracellular A A R F L L S V G S F V T P R F A V L P L P N-linked E G K R K D Q K glycosylation L P E I K K N E E G V T A Conserved phosphorylation L X P I E L D D site from rNIS E Q L N T C P T G E Q V W E P L N H G A G Predicted phosphorylation L D D S G K V X site R G G Figure 1 Secondary structure of hNIS.