研究代谢性内毒素血症对乳腺癌风险和进展的影响

Breast cancer is the most diagnosed cancer in women and the second most deadly, responsible for 670,000 deaths globally each year. Two main risk factors for breast cancer are aging and obesity, both of which are known to cause microbial dysbiosis and alterations in gut barrier function. These changes can result in chronic low levels of circulating lipopolysaccharides (LPS) in the blood, termed metabolic endotoxemia (ME). LPS interacts with toll-like receptor 4 (TLR4) resulting in the release of pro-inflammatory cytokines. Previously, our group has shown in non-cancerous postmenopausal women that obesity increases circulating LPS levels and other biomarkers of ME. However, in breast cancer patients (n=60), menopause status, not obesity, increases plasma LPS binding protein, anti-LPS IgG, and anti-LPS IgA. To investigate the impact of menopause, adiposity, and breast tumor presence on ME, we have employed a C57BL/6 murine study bearing E0771.Bo-ER+ breast tumors. Female 11-week-old C57BL/6 mice were placed on a low-fat control diet (10% kcal from fat, n=24) or a high-fat lard diet (60% kcal from fat, n=24). Subgroups of mice on each diet (n=8) underwent sham or ovariectomy (OVX) surgeries to model menopause. Additionally, we introduced fecal microbiota transplantation (FMT) groups (n=8) to examine the role of the gut microbiome. After 13 weeks of intervention, E0771.Bo-ER+ cells were injected into the mammary fat pad. We show the presence of a breast tumor (~400 mm 3 in tumor volume) significantly increases markers of ME. Furthermore, we show that a low-fat diet-derived FMT into high-fat diet consuming mice reduces breast tumor growth. LPS can vary in structure (displaying varying numbers of fatty acid chains on the lipid A toxin) and can differentially activate downstream TLR4 signaling. We show that various acylated isoforms of LPS can differentially activate NFκB and alter macrophage polarization and function. Overall, we aim to show whether the presence of breast cancer can directly influence ME and determine whether ME can impact breast cancer growth, thereby identifying a novel risk factor for breast cancer.