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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.

Despite advances in pharmacogenetics, the majority of heritability for treatment response cannot be explained by common variation, suggesting that factors such as epigenetics may play a key role. Regulatory genes, such as those involved in DNA methylation and transcriptional repression, are therefore excellent candidates for investigating antipsychotic treatment response. This study explored the differential expression of regulatory genes between patients with schizophrenia (chronic and antipsychotic-naïve first-episode patients) and healthy controls in order to identify candidate genes for association with antipsychotic treatment response. Seven candidate differentially expressed genes were identified, and four variants within these genes were found to be significantly associated with treatment response (DNMT3A rs2304429, HDAC5 rs11079983, and HDAC9 rs1178119 and rs11764843). Further analyses revealed that two of these variants (rs2304429 and rs11079983) are predicted to alter the expression of specific genes (DNMT3A, ASB16, and ASB16-AS1) in brain regions previously implicated in schizophrenia and treatment response. These results may aid in the development of biomarkers for antipsychotic treatment response, as well as novel drug targets.