(Download) "Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer" by Sasha Jasmine Beyer # eBook PDF Kindle ePub Free
eBook details
- Title: Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer
- Author : Sasha Jasmine Beyer
- Release Date : January 18, 2013
- Genre: Medical,Books,Professional & Technical,Science & Nature,
- Pages : * pages
- Size : 13660 KB
Description
The sodium iodide symporter (NIS) mediates iodide uptake into thyroid follicular cells for the biosynthesis of thyroid hormones and also serves as the basis of radioiodine therapy of thyroidcancer. NIS is also expressed in the majority of breast tumors, suggesting that breast cancer patients may also benefit from radionuclide therapy. However, only a fraction of NIS-positive breast tumors have detectable radionuclide uptake that may or may not be sufficient for therapy. The objective of this study was to elucidate mechanisms of NIS regulation in breast cancer such that strategies for selectively increasing NIS-mediated radionuclide therapy can be devised. Previous studies have reported that predominant intracellular localization of NIS caused by cell surface trafficking impairments likely accounts for low radionuclide uptake in breast cancer, as NIS must be localized at the cell surface in order to confer functional iodide uptake. However, cross-reactivity of antibodies appears to account for some intracellular NIS immunostaining, suggesting that NIS cell surface trafficking impairments may be overestimated. Moreover, cell surface NIS protein levels among breasttumors are low, with less than 29% strongly expressing cell surface NIS protein. Whether cell surface trafficking impairments or low cell surface NIS expression account for undetectable radionuclide uptake must be determined such that appropriate strategies for increasing cell surface NIS are developed. Strategies that differentially regulate NIS expression/activity between thyroid and breastcancer may not only increase NIS expression/activity in breast cancer, but also minimize iodide uptake in thyroid. KT5823, a staurosporine-related protein kinase inhibitor, increases thyroid stimulating hormone-induced NIS expression/function in thyroid cells, but reduces iodide transport rate and NIS affinity for iodide in trans-retinoic acid and hydrocortisone (tRA/H)-treated MCF-7 breast cancer cells. Moreover, while KT5823 has little effect on NIS glycosylation in thyroid cells, longer KT5823 treatments result in accumulated hypoglycosylated NIS and further reduction in RAIU in MCF-7/tRA/H cells in addition to other breast cancer cells overexpressing exogenous NIS. KT5823 may help elucidate mechanisms of NIS regulation at multiple levels, including expression, glycosylation and activity. In order to identify potential biomarkers associated with NIS expression, published cDNA microarray data were analyzed to elucidate gene expression tightly correlated with NIS mRNA expression among human breast tumors. However, the sensitivity of oligonucleotide microarray technology was not sufficient to detect variability in NIS mRNA expression in breast cancers. We then immunostained a TMA composed of 28 human breast tumors which had corresponding oligonucleotide microarray data available for each tumor for NIS protein such that gene expression highly associated with cell surface NIS protein level could be identified. Despite a limited number ofbreast tumors, our analysis identified cysteinyl-tRNA synthetase as a biomarker that is highly associated with cell surface NIS protein level in ER-positive breast cancer subtype. Taken together, gene expression profiling for genes associated with cell surface NIS protein levels within each breastcancer subtype may lead to novel targets for selectively increasing NIS expression/function in breastcancers patients.