Despite a regular spontaneous physical activity, a long-term high-fat diet promotes mammary cancer development in mice.

Abstract

International audienceBreast cancer is one of the most women common malignancies worldwide (1). Among the multiple risk factors, sedentary lifestyle, obesity and postmenopausal are correlated to estrogen and inflammation exposure during a lifetime (2). Physical activity protects against breast cancer development by affecting hormone levels, immune responses, and oxidative defences (3,4). This study aims was to assess the impact of long-term obesity on the benefits of physical activity in preventing and managing breast cancer during mammary tumorigenesis.Ovariectomized 35-week-old C57BL/6 mice were placed in an enriched environment to induce spontaneous physical activity and fed throughout the experiment with a high-fat diet (HFD). After 42 days (Short-term (ST), n=10) or 88 days (Long-term, LT, n=10) of exposure to HFD, syngenic mammary EO771 cells were implanted into the 4th mammary glands and the tumour growth was followed for 30 days. At sacrifice, the tumour microenvironment (TME) immune infiltrate and metabolic parameters were explored using flux cytometry, transcriptomic, enzyme activities and biochemical approaches. The data reported as mean SD were analysed by a Mann-Whitney test.The median survival was significantly reduced in the LT group compared to the ST group (22 days vs 25.5 days, p=0.0296). Whatever the group, the spontaneous physical activity (before tumor implantation (TI): 0.645±0.082 vs 1.065±0.076 km/mice/j; after TI: 0.0803±0.045 vs 0.965±0.217 km/mice/d) and the individual food intake was similar (before TI: 2.786±0.154 vs 2.835±0.066 g/d; after implantation: 2.264±0.208 vs 2.713±0.081 g/d) were similar. At the sacrifice, the visceral adipose tissue mass was higher in the LT group (1029.88±203.77 vs 1533.40±259.79 mg, p=0.04) while the skeletal muscle mass was reduced (354.20±12.79 vs 334.14±7.83 mg (ST group), p=0.0765). In the TME, among the total lymphocytes, the proportion of NK cells was reduced in the LT group (24.54±1.93 vs 0.24±0.09 %, p=0.05) as well as the TCD8+ one, (7.87±3.07 vs 1.01±0.28 %, p=0.002) while the proportion of T regulators tended to increase (0.02±0.01 vs 0.50±0.06 %Treg/T lymphocytes, p=0.1), leading to a collapse of the T8/Treg ratio (421.61±153.84 vs 2.62±1.31, p=0.03). The significant decrease in the tumour triglyceride content in the LT group (0.07±0.01 vs 0.01±0.01 mmol/g of tissue, p=0.0143) was accompanied with an enhanced activity of the glutathione reductase (165.46±5.81 vs 224.83±26.80 UI/mg of proteins, p=0.0286) and a decrease of the glutathione S transferase activity (295.40±15.10 vs 11.61±1.79 UI/mg of proteins, p=0.0143), markers of glutahione recycling involved in the oxidative stress management.In our experimental conditions, the LT HFD is associated with the tumor growth despite the spontaneous physical activity. LT HFD promotes a tolerogenic TME by increasing lipid consumption and oxidative stress and recruiting anti-tumour immune cells. The exploration of the tumor and skeletal muscles by the analysis of cytokines, myokines and free radicals could help to understand the inter-organ exchanges related to tumor development and muscle mass loss. In perspective, the combination of imposed physical activity with immunotherapy treatment could be envisaged to counteract the long-term effects of a hypercaloric diet.1.Sung H et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J Clin. mai 2021;71(3):209‑49. 2.Garcia-Estevez L, Moreno-Bueno G. Updating the role of obesity and cholesterol in breast cancer. Breast Cancer Res. déc 2019;21(1):35. 3.Swain CTV et al. Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones. Cancer Epidemiology, Biomarkers & Prevention. 1 janv 2022;31(1):16‑27. 4.Le Guennec D et al. Spontaneous Physical Activity in Obese Condition Favours Antitumour Immunity Leading to Decreased Tumour Growth in a Syngeneic Mouse Model of Carcinogenesis. Cancers. 23 déc 2021;14(1):59