Abstract 3130: Differential gene expression regulation by the RXR agonist V-125 in MMTV-Neu mammary tumors

Abstract Retinoid X receptors (RXRs) are nuclear receptors that play a pivotal role in regulating gene expression by forming homodimers and heterodimers with other nuclear receptors. When activated, RXRs influence various cellular processes, including cell differentiation, proliferation, and apoptosis. This regulatory activity makes RXR agonists promising candidates in cancer research. However, the specific gene expression changes induced by RXR agonists can vary depending on the compound, reflecting their unique interactions within cellular environments and signaling networks. In this study, RNA sequencing was performed to compare the molecular pathways activated by the novel compound V-125 and FDA-approved drug bexarotene in mammary tumors of a mouse model of HER2+ breast cancer (MMTV-Neu mice). By analyzing the transcriptomic profiles, we identified that each treatment differentially regulated cancer-relevant gene categories, including focal adhesion, regulation of actin cytoskeleton, and extracellular matrix-receptor interaction. The most significantly altered genes by V-125, including Lrrc26, Mgarp, Aldh1a3, and Colca2 are positively correlated with improved survival in breast cancer patients. While V-125 and bexarotene act on many common pathways, they induce distinct gene expression profiles. V-125 primarily targets focal adhesion and extracellular matrix-receptor interaction pathways, whereas bexarotene affects the regulation of actin cytoskeleton and NF-kappa B signaling pathways. We confirmed the significant differential expression (p<0.05) of key genes (Nrg1, Nfasc, Chi3l1, Slit2) at both the mRNA and protein levels using quantitative PCR (qPCR) and immunohistochemistry (IHC). Beyond cancer cells, RXR modulation influences the tumor microenvironment, including immune cells. Our transcriptomic analysis revealed that RXR agonist treatment affects pathways associated with macrophage activation and phagocytosis. This suggests the role of RXR in the polarization of macrophages, an important immune population related to breast cancer. To investigate this further, we utilized bone marrow-derived macrophages (BMDMs) to evaluate the impact of V-125 and bexarotene treatment on macrophage polarization toward a tumor-suppressive phenotype. Upon treatment, the polarization status of macrophages was assessed through gene expression analysis by qPCR. We observed that BMDMs treated with 300nM of either RXR agonist significantly (p <0.05) increased mRNA expression of IRF7 and TLR9, associated with a pro-inflammatory, anti-tumor phenotype. This comprehensive approach allowed us to determine the relative effectiveness of V-125 and bexarotene in modulating gene expression and polarizing macrophages toward a tumor-suppressive phenotype, providing valuable insights into their therapeutic potential and the underlying molecular mechanisms. Citation Format: Afrin Sultana Chowdhury, Lyndsey A. Reich, Christopher J. Occhiuto, Karen T. Liby. Differential gene expression regulation by the RXR agonist V-125 in MMTV-Neu mammary tumors [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 3130.