Abstract 3173: The NLRC4 inflammasome promotes breast cancer progression in diet-induced obese mice

Abstract

Abstract Obesity is not only a known risk factor for the development of ER+ breast cancer in postmenopausal woman, but is also associated with a poor clinical outcome across all subtypes of breast cancer. Obesity is also one of the only known risk factors for 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. One such hypothesis is 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 interleukin 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-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. Using a syngeneic orthotopic transplant model of breast cancer in C57Bl/6 mice (Py8119 cells and E0771 cells) we have shown that diet-induced obese (DIO) mice (mice fed a high fat diet) have increased tumor growth and metastasis compared to control mice (mice fed normal chow). Tumors from DIO mice have increased macrophage infiltration and caspase-1 activation compared to tumors from control mice. Additional studies have shown that treating DIO mice with an IL1R1 (the receptor for IL-1) blocking antibody reduces tumor growth to that observed in control mice. Furthermore, NLRC4 deficient DIO mice had reduced tumor growth (compared to wild-type DIO) mice, while there was no decrease in tumor growth in NLRP3 deficient DIO mice, indicating that NLRC4 inflammasome activation promotes breast cancer growth in obese mice. Finally, tumors from DIO mice had increased vascularization (as evidenced by an increase in CD31+ cells) compared to control mice, which was decreased in NLRC4 deficient mice or mice treated with the anti-IL1R1 antibody. This data indicates that obesity induced NLRC4 inflammasome activation in infiltrating macrophages in the mammary gland promotes breast cancer progression possibly through increased angiogenesis in the tumor microenvironment. Thus, targeting inflammasome activation or the IL-1/IL1R1 axis represents a rational target for the treatment of breast cancer in obese patients. Citation Format: Ryan Kolb, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Qing Xie, Fayyaz Sutterwala, Weizhou Zhang. The NLRC4 inflammasome promotes breast cancer progression in diet-induced obese mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3173. doi:10.1158/1538-7445.AM2015-3173