Abstract
The aberrant expression of human sodium iodide symporter (NIS) in breast cancer (BC) has raised the possibility of using targeted radioiodide therapy. Here we investigate modulation of endogenous, functional NIS expression by histone deacetylase inhibitors (HDACi) in vitro and in vivo. Luciferase reporter based initial screening of six different HDACi shows 2–10 fold enhancement of NIS promoter activity in majority of the cell types tested. As a result of drug treatment, endogenous NIS transcript and protein shows profound induction in BC cells. To get an insight on the mechanism of such transcriptional activation, role of Stat4, CREB and other transcription factors are revealed by transcription factor profiling array. Further, NIS-mediated intracellular iodide uptake also enhances substantially (p < 0.05) signifying functional relevance of the transcriptional modulation strategy. Gamma camera imaging confirms 30% higher uptake in VPA or NaB treated BC tumor xenograft. Corroborating with such functional impact of NIS, significant reduction in cell survival (p < 0.005) is observed in VPA, NaB or CI994 drug and 131I combination treatment in vivo indicating effective radioablation. Thus, for the first time this study reveals the mechanistic basis and demonstrates functional relevance of HDACi pre-treatment strategy in elevating NIS gene therapy approach for BC management in clinic.
Highlights
The current focus for development of targeted strategies in breast cancer (BC) is actively being researched to identify suitable therapy procedures that can eliminate BC cells with high specificity while minimizing the side effects
Further the minimal drug dose requirement to promote NIS gene expression was determined by luciferase reporter assays against increasing concentration of each drug using the established MCF-7 cell line expressing pNIS-Fluc[2]
Candidate Histone deacetylase inhibitors (HDACi) drug effects of Suberoylanilide hydroxamic acid (SAHA), Valproic acid (VPA) and CI994 at 48 hours revealed that except for the CI994 in thyroid cancer cell lines, all other non-breast cancer cell lines showed significant increase in NIS promoter activity (Supplementary Fig. 3B). These results suggest that the effect of HDAC inhibition may lead to NIS promoter activation by known mechanism of increased DNA binding ability, but for certain HDACi candidate the NIS promoter activation in breast cancer cells may happen through independent activation of factors than their thyroid counterparts
Summary
The current focus for development of targeted strategies in breast cancer (BC) is actively being researched to identify suitable therapy procedures that can eliminate BC cells with high specificity while minimizing the side effects In this context, the aberrant over-expression of human sodium iodide symporter (NIS) protein in breast cancer tissue is gaining great deal of attention. All-trans retinoic acid (atRA) alone or in combination with other glucocorticoids has been demonstrated to induce both NIS gene expression as well as iodide accumulation in MCF-7 cells and in vivo mouse model[12,13] Even though these findings suggest their potential clinical use, to date preclinical or clinical efficacy is not yet proven. Since NIS gene regulation in thyroid and breast tissue is differentially regulated, studying HDACi mediated modulation of NIS expression and function in vivo are of great interest. The study implicates that epigenetic transcriptional modulation strategy as a promishing approach, which may be extended for clinical trial in near future
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