Sulindac decreases basal-like mammary tumor burden and pro-inflammatory mediators in obese mice Public Deposited

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  • February 26, 2019
Creator
  • Khatib, Subreen
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Background: A hallmark of the metabolic dysregulation associated with obesity is a pro-inflammatory environment perpetuated by pro-inflammatory mediators including adipokines and growth factor signaling. We previously showed that inflammation and basal-like breast cancer (BLBC) growth are increased in chronically obese mice and these effects persist following significant weight loss. Hypothesis: We tested the hypothesis that Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), can reduce chronic obesity-related inflammation and subsequent BLBC growth in mice. Methods: Mice were administered a control diet (10 kcal % fat) or diet-induced obesity regimen (DIO, 60 kcal % fat). After 15 weeks on diet, DIO mice either continued on DIO diet or were switched to the low fat control diet to induce gradual weight loss, resulting in Formerly Obese (FOB) mice. Half of the mice in all three groups (CON, FOB, DIO, n=20/group) were randomized to receive Sulindac supplementation at 160 ppm in the diet, which remained constant across diets. Ten weeks after initiating Sulindac supplementation and weight loss in the FOB groups, serum was collected via submandibular bleed on a subset of fasted mice (n = 10-12/group). Thereafter, all mice were orthotopically injected with E0771 cells, a model of BLBC. Five mice/group were killed 4 weeks after tumor cell injection, while 12 mice/group continued in a survival study; these mice were killed when tumor size reached 1.2 cm in diameter. An NF-κB signaling targets PCR array (Qiagen) was completed on mammary fat pad harvested at end of study. Results: Sulindac supplementation in DIO mice significantly reduced serum insulin and leptin to levels statistically equivalent to both control and FOB mice. Interestingly, body weight and body fat percentage were unchanged between all supplemented and nonsupplemented counterparts (i.e. DIO vs. DIOSU). Sulindac supplementation in DIO mice (but not in CON or FOB mice) significantly reduced mean tumor volume relative to their nonsupplemented counterparts in the interim sac. Additionally, DIOSU had significantly increased percent survival compared to DIO, but no significant differences were observed in CON vs. CONSU or FOB vs. FOBSU. However, both FOB and FOBSU had significantly increased percent survival compared to DIO. The results of an NF-κB targets PCR array illustrated that Sulindac supplementation in DIO mice prevented losses in the expression of the NF-κB regulator TNF receptor-associated factor 2 (TRAF2) and also decreased expression of the apoptosis regulator X-linked inhibitor of apoptosis (XIAP) and two additional inflammation-related genes: tumor necrosis factor (TNF) and colony stimulating factor 1 (CSF1). Conclusions: Sulindac supplementation significantly reduced the obesity-associated metabolic mediators insulin and leptin and decreased mammary tumor burden in DIO but not CON or FOB mice. Furthermore, Sulindac supplementation did not modulate body weight, and had no significant tumor effect in normal weight mice, suggesting that Sulindac indeed offsets some of the pro-tumorigeneic effects of obesity. Analysis of our PCR array of NF-κB targets suggests that Sulindac prevents altered expression of pro-inflammatory cytokines and anti-apoptosis genes. Ongoing analyses of inflammatory surrogates, including circulating prostaglandins, mammary gland crown-like structures and cyclooxygenase-2 levels, will help to determine if Sulindac’s effects are mediated through its anti-inflammatory activity.
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  • In Copyright
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  • Funding: Summer Undergraduate Research Fellowship
  • Funding: Tom and Elizabeth Long Excellence Fund for Honors
Advisor
  • Hursting, Stephen
Degree
  • Bachelor of Science in Public Health
Honors level
  • Highest Honors
Degree granting institution
  • University of North Carolina at Chapel Hill
Extent
  • 30
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