Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer

SIMPLE SUMMARY: Different types of breast cancer are typically classified based upon expression of estrogen receptor, progesterone receptor, and epidermal growth factor receptor. One aggressive form of breast cancer is called triple-negative breast cancer (TNBC) because it lacks expression of these proteins. However, TNBC is also heterogeneous and can be further divided into distinct classes including an epithelial-like group and a mesenchymal-like group. The mesenchymal subtype may be vulnerable to therapeutic strategies that oxidize lipids and proteins. The aim of our study was to determine if silver nanoparticles (AgNPs) can cause these types of damage to selectively kill mesenchymal TNBCs. We found that AgNPs killed mesenchymal TNBCs by a mechanism involving lipid and protein oxidation without causing similar toxicity to normal breast cells. This study shows AgNPs are a specific treatment for mesenchymal TNBCs and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action. ABSTRACT: Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that induce lipid peroxidation or proteotoxicity may be particularly effective for various cancers with a mesenchymal phenotype such as CLBC, for which no specific treatment regimens exist and outcomes are poor. We hypothesized that silver nanoparticles (AgNPs) can induce proteotoxic stress and cause lipid peroxidation to a greater extent in CLBC than in BLBC. We found that AgNPs were lethal to CLBCs at doses that had little effect on BLBCs and were non-toxic to normal breast epithelial cells. Analysis of mRNA profiles indicated that sensitivity to AgNPs correlated with expression of multiple CLBC-associated genes. There was no correlation between sensitivity to AgNPs and sensitivity to silver cations, uptake of AgNPs, or proliferation rate, indicating that there are other molecular factors driving sensitivity to AgNPs. Mechanistically, we found that the differences in sensitivity of CLBC and BLBC cells to AgNPs were driven by peroxidation of lipids, protein oxidation and aggregation, and subsequent proteotoxic stress and apoptotic signaling, which were induced in AgNP-treated CLBC cells, but not in BLBC cells. This study shows AgNPs are a specific treatment for CLBC and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action.