Abstract 3971: The role of obesity-associated adipose tissue inflammation in breast cancer metastasis

Abstract

Abstract Although obesity is a known risk factor for breast cancer incidence, metastasis, and mortality, the mechanisms underlying this link remain elusive. This study therefore aims to uncover the relationship between obesity-associated adipose tissue and breast cancer metastasis by identifying specific inflammatory mediators in the adipose secretome. It is well known that obesity induces hypoxic conditions in the adipose tissue, stimulating an inflammatory response that ultimately creates a favorable environment for cancer cell growth and survival. The link between obesity-associated adipose inflammation and cancer metastasis, however, remains poorly described. We have previously shown that injection of basal-like E0771's, and claudin-low metM-Wnt-Lung and metM-Wnt-Liver metastatic breast cancer cell lines in mice fed a diet-induced obesity (DIO, 60% kcal from fat) diet displayed larger tumors with increased metastatic potential compared to lean mice fed a control (10% kcal from fat) diet. When diets were supplemented with Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), the enhancing effects of DIO on tumor growth and metastasis were mitigated. Gene expression microarray analysis of non-tumor bearing mammary fat pads from these mice revealed increased mammary expression of inflammation-related genes in tissues from DIO relative to control mice. Moreover, gene expression analysis of the tumor microenvironment from these mice revealed a signature of DIO-induced immunosuppression that was normalized by Sulindac supplementation. To further investigate the relationship between obesity-associated inflammation and breast cancer metastasis, we cultured our metastatic metM-Wnt-Lung, and metM-Wnt-Liver, and claudin-low, non-metastatic M-Wnt breast cancer cell lines with conditioned media (FCM) from the mammary fat pads of mice fed control, DIO, or DIO+Sulindac diets. We then conducted phenotypic assays to characterize differences in cell growth, proliferation, and metastatic potential. After normalizing the FCM concentrations to fat pad mass, we saw increased cell viability and migration in cells treated with FCM from DIO relative to control mice. Luminex assays identified several pro-inflammatory factors associated with the pro-cancer effects of FCM from DIO versus control mice, and additional characterization studies utilizing high-throughput proteomic screening and immune-depletion approaches are on-going. Taken together, our findings suggest an important role for the adipose secretome, and specifically inflammatory mediators, in obesity driven breast cancer progression. Citation Format: Lydia K. Eisenbeis, Shannon B. McDonell, Laura A. Smith, Alyssa J. Cozzo, Michael F. Coleman, Stephen D. Hursting. The role of obesity-associated adipose tissue inflammation in breast cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3971.