Inflammation and Tumor Progression: The Differential Impact of SAA in Breast Cancer Models
Daniel Wilhelm Olivier,
Carla Eksteen,
Manisha du Plessis,
Louis de Jager,
Lize Engelbrecht,
Nathaniel Wade McGregor,
Preetha Shridas,
Frederick C. de Beer,
Willem J. S. de Villiers,
Etheresia Pretorius,
Anna-Mart Engelbrecht
Affiliations
Daniel Wilhelm Olivier
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Carla Eksteen
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Manisha du Plessis
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Louis de Jager
Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Lize Engelbrecht
Central Analytical Facilities, Fluorescence Microscopy Unit, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Nathaniel Wade McGregor
Department of Genetics, Faculty of Agrisciences, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Preetha Shridas
Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
Frederick C. de Beer
Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
Willem J. S. de Villiers
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Etheresia Pretorius
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Anna-Mart Engelbrecht
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa
Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model. Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (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 wild-type 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 systemic inflammatory markers. Tumors from SAADKO mice overall had lower levels of SAA compared to tumors from wild-type mice, decreased apoptosis and inflammasome signaling, and little to no tumor necrosis. Conclusions: We demonstrated that systemic SAA1/2 stimulates the activation of the NLRP3 inflammasome in breast tumors, leading to the production of pro-inflammatory cytokines. This, in turn, promoted apoptosis and tumor necrosis but did not significantly impact tumor growth or histological grading.
