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Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer

Beyer, Sasha Jasmine
http://rave.ohiolink.edu/etdc/view?acc_num=osu1282141972

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
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 thyroid cancer. 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 breast tumors 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 breast cancer 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 of breast 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 breast cancer subtype may lead to novel targets for selectively increasing NIS expression/function in breast cancers patients.
Sissy Jhiang, PhD (Advisor)
Dawn Chandler, PhD (Committee Member)
Tsonwin Hai, PhD (Committee Member)
Kun Huang, PhD (Committee Member)
136 p.
Molecular Biology
radionuclide therapy; breast cancer; sodium iodide symporter

Recommended Citations

Citations

  • Beyer, S. J. (2010). Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1282141972

    APA Style (7th edition)

  • Beyer, Sasha. Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1282141972.

    MLA Style (8th edition)

  • Beyer, Sasha. "Modulation of Cell Surface Sodium/Iodide Symporter Expression and Activity in Breast Cancer." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1282141972

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.