Abstract B20: Obesity-induced Nlrc4 inflammasome promotes angiogenesis in breast cancer

Obesity, which impacts 36% of adults in the U.S., is associated with an increased risk of ER-positive breast cancer in postmenopausal women, increased incidence of the more aggressive triple negative breast cancer, increased risk of developing invasive ductal carcinoma (IDC) versus ductal carcinoma in situ (DCIS; non-invasive) and a worse clinical outcome. There have been many hypotheses to explain this link between obesity and breast cancer, but a causal mechanism is still largely missing. Here, using two syngeneic orthotopic transplant models in C57Bl/6 mice, we examined the role of obesity-associated inflammasome activation/IL-1 signaling in obesity-driven breast cancer progression. Our results show that the tumor microenvironment under the conditions of obesity promotes Nlrc4 inflammasome activation in tumor-infiltrating myeloid cells, which in turn leads to IL-1β activation which promotes tumor progression. Further studies show that obesity-induced Nlrc4 inflammasome activation/IL-1β promotes increased angiogenesis and upregulation of Vegfa, primarily in adipocytes. Finally, treatment of mice with Metformin inhibited obesity-associated angiogenesis and breast cancer progression. This data provides evidence for obesity-induced Nlrc4 inflammasome mediated activation of IL-1β as a causal mechanism for obesity-driven breast cancer progression and a rationale for blockade of IL-1 signaling, the use of anti-angiogenesis therapies, or treatment with metformin in obese breast cancer patients. Citation Format: Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M. Janowski, Qing Xie, Kathleen R. Markan, Wei Li, Matthew J. Potthoff, Enrique Fuentes-Mattei, Leslie G. Ellies, Michael Knudson, Mong-Hong Lee, Sai-Ching Jim Yeung, Suzanne L. Cassel, Fayyaz S. Sutterwala, Weizhou Zhang. Obesity-induced Nlrc4 inflammasome promotes angiogenesis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B20.