Impact of high fat diet and physical activity on tumor’s inflammation and oxidative stress in a model of C57BL/6 mouse

Background: Accumulative evidences link breast cancer development to obesity. Several studies have demonstrated an increase of Reactive Oxygen Species (ROS) production and a decrease of antioxidant capacity resulting in an oxidative stress and a low-grade inflammation in overweight. Many epidemiologic studies have found an inverse association between physical activity and breast cancer risk, particularly for post-menopausal woman. Therefore, biological mechanisms underlying the relationship between oxidative stress, low-grade inflammation due to obesity and breast cancer are poorly understood. Objectives: In this study, we proposed to explore the link between oxidative stress, inflammation and mammary tumor growth in a model of elderly ovariectomised mice feeding with high fat diet (HFD) and housing in enriched environment (EE). Materials and methods: C57BL/6 mice (33 weeks) were divided in 2 groups, both fed with HFD: one housing in EE for stimulate spontaneous physical activity and the other in standard environment (SE). After eight weeks, mammary tumor cells (EO771) were implanted into the fourth right mammary gland by fat-pad technique. Tumor growth was measured twice a week with a caliper. Based on tumor-volume limit point, animals were sacrificed during a 4 weeks time-window (between 3rd and 6th week after tumor implantation). Tumors were recovered for antioxidant enzymes determination (i.e. heme oxygenase (HOx), thioredoxine reductase (TRx), glutathione reductase (GR), glutathione S-transferase (GST), glutathione assays…) and for measurement of inflammation (lipid peroxidation, isoprostanes and cyclooxygenase 2 (COX2) activity). Results: After 2 weeks of tumor growth, mice housing in EE presented lower tumor volume (1241 ± 743 vs 634 ± 388 mm3, p = 0,039). At the sacrifice, despite a similar weight (1,44 ± 0,64 vs 1,87 ± 0,64 g) between SE and EE, some differences in anti-oxidant response were observed. HOx and TRx activities were decreased in EE conditions (26 ± 12 vs 18 ± 6 mUI/g, p= 0,038 and 68 ± 28 vs 62 ± 21 mUI/g, p = 0,111), contrary to GR and GST activities which were not affected by EE. The reduced/total glutathione ratio tended to increase with EE (0,25 ± 0,19 vs 0,28 ± 0,12, p = 0,117). Regarding tumor inflammation, lipid peroxidation was not impacted by EE while isoprostane content increased (3,9 ± 5,7 vs 7,1 ± 13 ng/g, p= 0,069) and COX2 activity tended to reduce in this condition (7,6 ± 2,9 vs 6,3 ± 3,2 mUI/g, p = 0,083). Conclusion: An increase of reduced glutathione and a decrease of thioredoxine reductase activity correlate to a lesser requirement for protection in cells. The reducing of COX2 and HOx activities seems to demonstrate an inflammation decrease. Taken together, these results suggest that physical activity is able to reduce tumor growth, due to a modification in tumor oxidative stress and inflammatio