Abstract 4750: Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer

The sodium iodide symporter (NIS, encoded by SLC5A5) is exploited in thyroid cancer to uptake radioiodide. NIS appears to function in mammary epithelial cells, being upregulated during lactation, and offers the possibility of a novel breast cancer (BrCa) radiotherapy. Unfortunately, NIS appears repressed in BrCa, and therefore we are examining mechanisms to restore its expression and function. Retinoic Acid Receptor alpha (RARα) upregulates SLC5A5, and pre-clinical studies suggest this is epigenetically corrupted in BrCa. To investigate RARα-dependent epigenetic control of SLC5A5 levels we identified differentially expressed RARα coregulators in TNBC tumors in the TCGA BrCa cohort. This identified upregulation of PRAME, a known RARα co-repressor that interacts with histone deacetylase (HDAC) enzymes. We modulated PRAME expression using CRISPR methods in a panel of luminal A, luminal B and TNBC BrCa cell lines (MCF-7, T47-D, ZR-75-1, AU565 and MDA-MB-231). Elevated PRAME expression significantly repressed the antiproliferative response to ATRA (a pan-RAR ligand) and AM580 (a RARα-selective ligand). RNA-Seq confirmed that increased PRAME expression reduced by approximately half the number of significantly regulated genes in response to ATRA and AM580. For example SLC5A5 and a significant number of RARα-canonical target genes were upregulated in MCF-7 and AU565 cells and the magnitude was significantly reduced by elevated PRAME. In MDA-MB-231 cells elevated PRAME expression led to transrepression of numerous genes including SLC5A5 in response to ATRA and AM580. Gene set enrichment analyses also supported a significant role for PRAME to uniquely shape ATRA signaling by increasing inflammatory networks (MCF-7 and AU565) and decreasing estrogen (MCF-7) and TNFA (MDA-MB-231) signaling. Ongoing studies are repressing PRAME and examining its impact on activating and repressing histone marks. In a parallel orthogonal approach we have sought to stabilize NIS expression by targeting valosin-containing protein (VCP) that induces NIS proteolysis. We tested VCP inhibitors in combination with the HDAC inhibitor SAHA or the transcriptional potentiator, disulfiram metabolite Cu(DDC)2 in the same cell lines. Remarkably, in MDA-MB-231 cells, Cu(DDC)2 combined with the VCP inhibitor CB5339, significantly increased NIS expression and radioiodide uptake leading to a prominent decrease in cell proliferation and survival. These studies, along with ongoing drug strategies in TNBC xenograft and PDX tumors, combine to support the concept that SLC5A5/NIS expression can be restored and offer the possibility of promoting radioiodide as a novel BrCa radiotherapy. Citation Format: Khalid B. Mir, Katie Brookes, Martin L. Read, Daniel G. Stover, Mathew D. Ringel, Christopher J. McCabe, Moray J. Campbell. Epigenetic approaches to deliver a targeted radiotherapy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4750.