Abstract P76: α-Arrestin ARRDC3 Regulates TNF-α-Mediated Signaling Through TNFR1 in Triple Negative Breast Cancer

Abstract

Triple negative breast cancers (TNBC) account for 10-20% of all breast cancer diagnoses in the United States and are noted for their aggressive reoccurrences and complex molecular heterogeneity. Although the mainstay of TNBC treatment is chemotherapy and radiation therapy, over half of TNBC patients are susceptible to chemoresistance. Furthermore, the lack of traditional hormone receptors on TNBC cells limit therapeutic targeting and therefore make TNBC critical for pharmacological development. At the molecular level, dysregulated signaling notably drives oncogenic function as a result of modified receptor expression, agonist activity, or post-translational modification status of intracellular effectors. Arrestin domain-containing protein 3 (ARRDC3) is a mammalian scaffolding protein important for receptor endolysosomal trafficking and degradation. We previously showed that ARRDC3 regulates G-protein coupled receptor-mediated signaling, trafficking, and metastases in invasive breast cancer. However, ARRDC3 protein expression is decreased across various invasive breast cancer cell lines. In new work we extend investigation of ARRDC3 as an emerging tumor suppressor in regulation of inflammatory signal transduction in invasive breast cancer. Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that drives signaling in invasive breast cancer through tumor necrosis factor receptor superfamily member 1A (TNFR1). Our work reveals that re-expression of ARRDC3 affects basal expression of TNFR1 and the rate of TNFR1 degradation following TNF-α stimulation. We also show that ARRDC3 re-expression is sufficient to decrease both TNF-α-mediated p38 phosphorylation and cytokine expression. Together, these data suggest a novel tumor suppressor role for ARRDC3 in the context of TNFR1-mediated signaling and cytokine regulation in TNBC. Our ultimate goal is to understand how ARRDC3 modulates the tumor microenvironment to identify alternative therapies for patients who experience pro-inflammatory and dysregulated oncogenic signaling.