Abstract 1321: Effects of sulindac on inflammatory and cellular responses in mammary tumors from obese mice

Abstract

Abstract Background: Breast cancer is the second leading cause of cancer-related death in US women. Obesity (BMI > 30 kg/m2) promotes breast cancer incidence, progression, and mortality in women of all ages. The prevalence of obesity in the US has increased dramatically over recent decades and continues to rise. Although obesity is associated with increased adipose tissue inflammation and metabolic dysfunction the exact mechanisms regulating obesity-exacerbated tumor growth are relatively unknown. Nonsteroidal anti-inflammatory drugs (NSAIDs), like sulindac, inhibit cyclooxygenase-1 and cyclooxygenase-2 and modulate the secretion of pro-inflammatory cytokines. The purpose of this study was to investigate the mechanisms underlying the anticancer effects of sulindac in our E0771 mouse model of obesity and mammary tumor growth. Methods: C57BL/6J mice were fed either a high-fat diet (n=16) or a low-fat control diet (n=12) for 15 weeks. Half of the control (n=6) and DIO (n=8) mice were then treated with 140 ppm sulindac in their respective diets for 4 weeks prior to orthotopic injection of 20,000 E0771 cells. Tumors were harvested and weighed, and serum was collected 4 weeks following injection. Bulk transcriptional profile analysis was performed on E0771 tumors from untreated control and DIO mice relative to sulindac-treated control and DIO mice using Affymetrix microarrays followed by gene set enrichment analysis (GSEA) to identify significantly enriched gene sets. Serum cytokine levels were measured in all mice using the Bio-Plex Pro mouse chemokine panel 33-plex; multiple linear regression was conducted to determine cytokines associated with mammary tumor size, independent of diet or treatment group assignment. Results: DIO mice had increased tumor weight relative to control mice, while sulindac decreased tumor weight in DIO but not control mice. GSEA analysis revealed only one gene set upregulated in the DIO tumors relative to control or DIO sulindac tumors. Immune-related gene sets were commonly enriched in tumors from control and DIO sulindac relative to DIO mice, suggesting that sulindac restored immune signaling in tumors from DIO mice. Leading edge analysis of the significantly enriched gene sets showed that: 1) the reversal of DIO-mediated immunosuppression by sulindac occurred via principally overlapping genes; and 2) cytokine and immune genes predominate the transcriptional effects of sulindac treatment in DIO mice. Sulindac also modified circulating serum cytokine levels, but multiple linear regression showed that cytokine levels were not independently predictive of tumor weight in our study. Conclusions: The study suggests that sulindac can reverse transcriptional changes in mammary tumors from obese mice and restore immunosurveillance. Sulindac, or potentially other NSAIDs, may protect against obesity–driven mammary tumor growth via remodeling of antitumor immune function. Citation Format: Morgan E. Cody, Shannon B. McDonell, Qing Shi, Elaine M. Glenny, Michael F. Coleman, Stephen D. Hursting. Effects of sulindac on inflammatory and cellular responses in mammary tumors from obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1321.