RXR Agonist V-125 Induces Distinct Transcriptional and Im-munomodulatory Programs in Mammary Tumors of MMTV-Neu Mice Compared to Bexarotene

Background: The retinoid X receptor (RXR) is a ligand-activated nuclear receptor that heterodimerizes with numerous partners to regulate diverse transcriptional programs. RXR agonists, in-cluding the FDA-approved drug bexarotene, show anti-tumor activity but are limited by adverse side effects. V-125 is a next-generation RXR agonist engineered for improved se-lectivity, pharmacokinetics, and reduced lipogenic effects. This study compares the mo-lecular and functional effects of V-125 and bexarotene in HER2⁺ breast cancer models. Methods: Female MMTV-Neu mice bearing mammary tumors were treated with control, V-125 (100 mg/kg diet), or bexarotene (100 mg/kg diet) for 10 days. RNA sequencing was used to identify differentially expressed genes and pathways. Candidate targets were validated by qPCR and immunohistochemistry (IHC). Immune modulation was evaluated by IHC staining for CD8 cells and CD206⁺ macrophages in tumors to capture the tumor microen-vironment. Functional assays in JIMT-1 human HER2⁺ cells assessed RXR target activation and clonogenic potential in tumor cells. Results: V-125 induced broader transcriptional changes than bexarotene, including selective up-regulation of Nrg1, Nfasc, Lrrc26, and Chi3l1 genes associated with improved patient sur-vival. Pathway analysis revealed regulation of immune activation, cancer signaling, and lipid metabolism. Both V-125 and bexarotene suppressed colony formation in JIMT-1 cells, confirming previous observations about RXR-dependent inhibition of tumor cell growth. Moreover, V-125 in vivo had distinct capabilities to increase CD8 cell infiltration and reduced CD206⁺ macrophages, whereas bexarotene did not. Conclusion: V-125 but not bexarotene reprograms tumor transcriptional programs and the immune landscape in an anti-tumor manner in MMTV-neu mouse model and in in vitro models of HER2⁺ breast cancer. This highlights its promise as a selective RXR agonist with anti-tu-mor and immunomodulatory activity in HER2⁺ breast cancer.