Heparanase Links Obesity-Associated Inflammation and Breast Cancer Via Modulation of Macrophage Responses

Obesity profoundly affects breast cancer progression and inflammatory responses are critical contributors to the obesity-breast cancer link. While function of immunocytes (largely, macrophages) and their derived cytokines in coupling obesity-associated inflammation and breast cancer is well characterized, the involvement of extracellular matrix (ECM) and its enzymatic remodeling in these phenomena remains under-investigated. The purpose of our study was to elucidate the role of heparanase, mammalian endoglycosidase that cleaves heparan sulfate (chief ECM polysaccharide) in the obesity-breast cancer link.

Utilizing murine model of high fat diet-induced obesity we detected elevated heparanase levels in orthotopic breast tumors growing in obese mice. Furthermore, applying heparanase-deficient (Hpse-KO) mice we found that obesity accelerates breast tumor progression in wild type (wt) but not in Hpse-KO mice. Importantly, while 2-fold increase in infiltration of macrophages was observed in tumors grown in wt obese vs. wt lean mice, no difference in macrophage infiltration was detected in tumors growing in Hpse-KO obese vs. Hpse-KO lean mice. Moreover, in vitro heparanase enzyme conferred pro-cancerous phenotype to macrophages stimulated by saturated fatty acids (sFA), which are typically elevated under obesestate .

In conclusion, our data underscore previously unknown role of heparanase in promoting breast tumorigenesis under obese conditions. It appears that the enzyme (which is induced in breast carcinoma tissue by estrogen-dependent mechanism), creates tumor-promoting inflammatory microenvironment by directing pro-cancerous action of macrophages.

Given intensive development and ongoing clinical testing of heparanase inhibitors our findings are expected to offer future strategies toward a more efficacious therapy in rapidly growing fraction of breast carcinoma patients with increased body weight.