Inflammation and Tumor Progression: The Differential Impact of SAA in Breast Cancer Models

Author:

Olivier Daniel Wilhelm1ORCID,Eksteen Carla1ORCID,Plessis Manisha du1,de Jager Louis23,Engelbrecht Lize4ORCID,McGregor Nathaniel Wade56,Shridas Preetha7ORCID,de Beer Frederick C.7,de Villiers Willem J. S.18ORCID,Pretorius Etheresia1ORCID,Engelbrecht Anna-Mart19ORCID

Affiliation:

1. Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa

2. Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa

3. National Health Laboratory Service, Tygerberg Hospital, Cape Town 7505, Western Cape, South Africa

4. Central Analytical Facilities, Fluorescence Microscopy Unit, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa

5. Department of Genetics, Faculty of Agrisciences, Stellenbosch University, Stellenbosch 7600, Western Cape, South Africa

6. Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, Western Cape, South Africa

7. Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA

8. Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7505, Western Cape, South Africa

9. Department of Global Health, African Cancer Institute (ACI), Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch 7505, Western Cape, South Africa

Abstract

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.

Funder

National Research Foundation

South African Medical Research Council

Cancer Association of South Africa

Publisher

MDPI AG

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