title: Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation.
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 (131)I 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.
authors.affiliation: Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Madhura G
authors.initials: MG
authors.lastname: Kelkar
authors.affiliation: Department of Nuclear Medicine, Kyungpook National University, Republic of Korea.
authors.forename: Kalimuthu
authors.initials: K
authors.lastname: Senthilkumar
authors.affiliation: Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Smita
authors.initials: S
authors.lastname: Jadhav
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Nuclear Medicine, Kyungpook National University, Republic of Korea.
authors.forename: Beyong-Cheol
authors.initials: BC
authors.lastname: Ahn
authors.affiliation: Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: De
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D051379:Mice; D011401:Promoter Regions, Genetic; D050797:STAT4 Transcription Factor / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D007457:Iodine Radioisotopes; D050797:STAT4 Transcription Factor; D027981:Symporters; D000099209:Sodium-Iodide Symporters