Abstract
Retinoid X receptors (RXRs) are a class of nuclear receptors that regulate transcription of genes associated with inflammation, proliferation, and apoptosis. Thus rexinoids, pharmacological agonists of these receptors, have significant potential for use to treat cancer. The rexinoid bexarotene is FDA approved for cutaneous T-cell lymphoma and has been tested in clinical trials for metastatic breast cancer. While bexarotene failed to achieve approval for this indication, some patients responded to treatment despite late-stage, aggressive disease. We have made chemical modifications to bexarotene in order to improve its potency and to reduce toxicity. The new lead rexinoid, V-125, is effective for prevention and treatment in the MMTV-Neu mouse model of HER2+ breast cancer. The mechanism of rexinoid-induced tumor regression remains unclear, but rexinoids modulate the immune microenvironment rather than cancer cells. We hypothesize that V-125 skews macrophages from a tumor-promoting to tumor-suppressive phenotype. To test, bone marrow-derived macrophages were skewed toward a tumor-promoting phenotype, treated with V-125, and analyzed by qPCR for changes in expression of genes associated with macrophage phenotype and function, such as iNOS and Arg1. We also completed immunohistochemical staining on tumor sections from MMTV-neu mice treated with V-125 (100 mg/kg diet for 10 days). Biomarkers included CD206, a mannose receptor indicative of a tumor-promoting macrophage phenotype; programmed death-ligand 1 (PD-L1), an immune checkpoint protein; and cleaved caspase 3 (CC3), a marker of apoptosis. Results from these studies will further elucidate the immunomodulatory effects of V-125, a promising treatment for breast cancer.