Abstract LB224: The potential effect of chronically increased endotoxin levels on breast carcinoma progression in obese patients.

Obesity serves as a risk factor for estrogen-dependent postmenopausal breast cancer (BC). While the exact association occurring between these two disease states remains unknown, obesity-associated inflammation is thought to be the most likely contributing factor. In addition, obesity has been correlated to changes in gut microbiota composition and a subsequent chronic increase in bacterial endotoxin (lipopolysaccharide [LPS] - canonic ligand of toll-like receptor 4 [TLR4]) blood levels. It was recently shown that BC cells intrinsically express TLR4 and such expression has been associated with decreased patient survival as well as increased tumor growth. We hypothesized that obesity-associated endotoxemia may contribute to BC progression by utilizing TLR-dependent mechanisms and exerting cancer-promoting effects directly (on carcinoma cells) and indirectly (triggering abnormal activation of macrophages). Utilizing a chronic metabolic endotoxemia and breast cancer murine model as well as in vitro experimental systems, we found that continuous exposure to low concentrations of LPS not only promotes BC progression in vivo but stimulates BC cell growth in culture through the activation of key breast cancer-promoting signaling pathways (Stat3, Akt, ERK1/2). Obesity has reached epidemic proportions globally, where elucidation of the molecular mechanisms underlying breast tumor-promoting action of obesity has become of vital importance. Improving the understanding of such mechanisms has the potential to reveal improved efficacious therapy regimens and prevention strategies in a rapidly growing population of obese, breast cancer patients. Citation Format: Amichay Meirovitz, Daniela Nahmias, Esther Hermano, Ofra Maimon, Tamar Peretz, Michael Elkin. The potential effect of chronically increased endotoxin levels on breast carcinoma progression in obese patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB224.