Chronically increased endotoxin levels in obese patients: possible effect on breast carcinoma progression.

Obesity is associated with increased risk of estrogen-dependent postmenopausal breast cancer (BC). While several factors have been proposed to be involved in coupling obese state and BC, obesity-associated inflammation is amongst the most likely contributors. Obesity is also associated with a change in gut microbiota composition and chronic increase in blood levels of bacterial endotoxin (lipopolysaccharide [LPS] - canonic ligand of toll-like receptor 4 [TLR4]). It was recently shown that BC cells per se express TLR4, and its expression/activation is associated with decreased patient survival/increased tumor growth. We hypothesized that obesity-associated endotoxemia may contribute to BC progression under obese conditions, acting through TLR-dependent mechanisms and exerting pro-cancerous effects directly (on carcinoma cells) and indirectly (triggering abnormal activation of macrophages). Utilizing mouse model of chronic experimental metabolic endotoxemia and breast cancer, along with in vitro experimental systems, we found that continuous exposure to low concentrations of LPS, promotes BC progression in vivo and stimulates BC cell growth in culture, through activation of key breast cancer-promoting signaling pathways (Stat3, Akt, ERK1/2).

As prevalence of obesity has reached pandemic proportions, dissection of molecular mechanisms underlying breast tumor-promoting action of obesity will expected to pave the way for more efficacious therapy/prevention strategies in the rapidly growing population of obese breast cancer patients.