HPSE and metabolic disease: At the same time, several diabetic milieu constituents, known to increase heparanase expression/secretion in endothelial cells and immunocytes [47–51], may augment the expression of the enzyme in stromal elements of the tumor, suggesting that a self-sustaining circuit may exist in metabolic disorder-related ER positive breast cancer, where estrogen, and components of the diabetic milieu induce heparanase, while heparanase acts in tandem with elevated insulin to promote cell growth via enhanced INSR signaling.