Abstract 4098: Inflammasome activation in obesity-associated breast cancer progression

Abstract

Abstract The purpose of this research is to determine the role of inflammasome-mediated production of interleukin(IL)-1β in obesity-associated breast cancer progression. Previous studies have shown that obesity is a risk factor for both developing breast cancer and breast cancer progression. Obesity is also associated with the development of invasive ductal carcinoma (IDC) versus ductal carcinoma in-situ (DCIS; non-invasive). A number of hypotheses have been proposed to explain the association between obesity and breast cancer progression. It has been hypothesized that the chronic inflammation in adipose tissue associated with obesity, especially adipose tissue in the mammary glands, creates a microenvironment that promotes breast cancer progression by acting as a reservoir of pro-inflammatory cytokines (including IL-1β and IL-6). One source of pro-inflammatory cytokines in adipose tissue is activated inflammasomes in infiltrating macrophages. Inflammasomes are multiprotein complexes whose main function is the activation of IL-1β and IL-18 during inflammation via Caspase 1 (Casp1)-mediated proteolytic cleavage. Chronic inflammation, Nlrp3 inflammasome activation and IL-1β are thought to be a major cause of obesity-associated insulin resistance and are involved in many human diseases including type-2 diabetes and cancer. However, the mechanism linking obesity and breast cancer progression remains unknown. We hypothesize that obesity-induced inflammasome activation in mammary adipose tissue results in active IL-1β which in turn promotes breast cancer progression. To determine the role of inflammasome activation in obesity-associated breast cancer progression, we will use inflammasome-deficient mice or neutralizing antibodies to inhibit IL-1 signaling in a syngeneic orthotopic transplant model of Py8119 cells in obese mice (mice fed a high fat diet). Our results show that Py8119 tumors have increased tumor growth and metastasis in obese mice compared to lean mice (mice fed normal chow). Furthermore, tumors from obese mice had increased expression of IL-1β and its receptor IL1 receptor 1 (IL1R1) as well as increased Casp1. Tumors from obese mice also had increase in M1 (which can secrete IL-1β) and M2 (which can be recruited in response to IL-1β signaling) tumor-infiltrating macrophages. Finally, inhibition of IL-1β signaling using an IL1R1 neutralizing antibody or Casp1 deficiency results in reduced tumor growth in obese mice. In conclusion, our results suggest that obesity-induced inflammasome activation promotes breast cancer progression in obese mice. Targeting inflammasome activation or neutralizing the IL-1/IL1R axis represents a rational therapy to treat obese patients with invasive breast cancer. Citation Format: Ryan Kolb, Yinghong Liu, Qing Xie, Nicholas Borcherding, Wei Li, Weizhou Zhang. Inflammasome activation in obesity-associated breast cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4098. doi:10.1158/1538-7445.AM2014-4098