SFEBES2026 Poster Presentations Endocrine Cancer and Late Effects (12 abstracts)
RNA-seq analysis of transcriptional co-regulators of NIS in a murine model of triple negative breast cancer
Katie Brookes 1 , Martin L. Read 1 , Davina Banga 1 , Khalid Bashir 2 , Jessica S. Fear 1 , Benjamin Small 3 , Vinodh Kannappan 3 , Weiguang Wang 3 , Adam Jones 4 , Kavitha Sunassee 4 , Daniel G. Stover 5 , Matthew D. Ringel 5 , Vicki E. Smith 1 , Moray J. Campbell 2 & Christopher J. McCabe 1
1University of Birmingham, Birmingham, United Kingdom; 2Karmanos Cancer Institute, Detroit, USA; 3University of Wolverhampton, Wolverhampton, United Kingdom; 4King’s College London, London, United Kingdom; 5The Ohio State University College of Medicine and Comprehensive Cancer Center, Ohio, USA
Introduction: The sodium iodide symporter (NIS; SLC5A5) is the sole transporter of iodide, exploited in radioiodide treatment of differentiated thyroid cancer. NIS is expressed in breast cancer (BrCa), but its intracellular retention prevents sufficient radioiodide uptake for tumoural ablation. Pre-clinical studies suggest that upregulation of SLC5A5 is promoted by retinoic acid receptor alpha (RARα), and that this mechanism is epigenetically corrupted in BrCa via upregulation of the RARα co-repressor PRAME. We recently reported that the histone deacetylase (HDAC) inhibitor SAHA - combined with the disulfiram metabolite Cu(DDC)2 - significantly increased NIS function in MDA-MB-231 orthotopic tumours. Here, we employed RNA-seq analysis of these tumours to determine whether transcriptional co-regulators impact NIS expression in BrCa.
Methods: Global changes in gene expression in response to SAHA and Cu(DDC)2 were appraised by RNA-seq analysis. Differentially expressed genes (DEGs) were identified and analysed using DSeq2 and DAVID.
Results: PRAME-overexpressing MDA-MB-231 cells demonstrated significantly lower anti-proliferative responses to ATRA (pan RAR ligand) and AM580 (RARa ligand). PRAME overexpression led to trans-repression of RARα canonical target genes and SLC5A5 in response to ATRA. We therefore established a panel of BrCa cell lines (MDA-MB-231, SUM52, AU565, SKBR3) stably transfected with either CRISPR-VP64 (activator) or CRISPR-KRAB (repressor), measuring the expression of SLC5A5 and the ability to transport radioiodide. Gene ontology enrichment analysis and pathway mapping of in vivo BrCa tumours treated with SAHA and Cu(DDC)2 highlighted transcriptional regulation as the most significantly altered biological process (474/1230; q=9.05x10-15) and chromatin remodelling linked to HDAC4 (q=2.5x10-7). Interestingly, 1081 genes regulated by RARα were significantly dysregulated due to drug treatment (q=3.21x10-84).
Discussion: These studies reveal that our drug strategies to enhance NIS function in orthotopic breast tumours are accompanied by unexpectedly potent transcriptional activation, yielding further insight into the mechanisms that control SLC5A5 expression in breast cancer.
Volume 117
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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