Heparanase accelerates obesity-associated breast cancer progression.

Obese women have higher risk of bearing breast tumors which are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g. free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages - key cellular players in obesity-related cancer progression. While the contribution of macrophages to pro-neoplastic effects of obesity is well-documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program which occurred concurrently in adipose and tumor tissue, and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages (atM) to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of pro-cancerous phenotype by tumor-associated macrophages (TAM), resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing anti-heparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients.