Beyond the acute-phase response: systemic Serum Amyloid A 1/2 promotes inflammasome activation, apoptosis, and necrosis in breast cancer

Abstract

Background Past research has identified the family of Serum Amyloid A (SAA) proteins to be intricately involved in inflammatory signaling and various disease pathologies. In cancer patients, SAA proteins have been reported to be upregulated in blood and tumor tissue, correlating in many instances with disease progression. However, the exact role of SAA proteins in cancer pathology remains to be fully elucidated. We, therefore, investigated systemic SAA1 and SAA2 (SAA1/2) in modulating the inflammasome, cell cycle, apoptosis, and epithelial-to-mesenchymal transition (EMT). Methods Breast cancer allografts were established in wild-type mice (WT), and mice lacking the SAA1/2 orthologs (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice assessed with a multiplex assay, and tumor molecular biology and histology characterized with western blotting and H&E histological staining. Results WT tumor-bearing mice had increased levels of plasma SAA compared to WT control mice, while SAADKO control and tumor-bearing mice presented with lower levels of SAA in their plasma. SAADKO tumor-bearing mice also displayed significantly lower concentrations of the systemic inflammatory markers, IL-1β, IL-6, and IL-10 compared to WT tumor-bearing mice. Tumors from SAADKO mice overall had lower levels of SAA compared to tumors from WT mice, decreased apoptotic (cytochrome c, caspases 9/3, PARP), and inflammasome (NFκB, caspase 1, NLRP3) signaling, with little to no tumor necrosis. Conclusions We show that systemic SAA1/2 promotes the activation of the NLRP3 inflammasome in breast cancer tumors and the generation of pro-inflammatory cytokines, which promotes apoptosis and tumor necrosis. Based on these findings, we hypothesize that SAA1/2-mediated necrosis is due to NLRP3-mediated pore formation in membranes, while apoptosis signaling is likely mediated via the TIF-IA-NF-κB-apoptosis axis.