THE ROLE OF OBESITY-ASSOCIATED EXTRACELLULAR MATRIX REMODELING IN MACROPHAGE ACTIVATION AND POTENTIAL IMPLICATIONS TO BREAST CANCER

Abstract

Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether obesity-associated ECM-remodeling affects macrophage phenotype is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in people with obesity. Utilizing clinical samples, computational approaches and in vitro models, this study quantified the relative abundance of pro (M1)- and anti (M2)-inflammatory macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2-biased than M1-biased macrophages across all body mass index (BMI) categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis (GSEA) suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages (TAMs). These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obesity-dependent ECM remodeling directly stimulate M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, our data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to TAMs, which may contribute to the link between obesity and breast cancer.