Collectively, these data highlight a novel mechanism through which interplay between elements of the obesity-associated BC microenvironment, both cellular (i.e., Mφ, upregulating ERα expression; carcinoma cells, supplying heparanase) and extracellular (obese milieu components, HS), influences estrogen sensitivity—a critical component in hormone-related cancer progression and resistance to endocrine therapy. Here, HPSE is linked to obesity due to melanocortin 4 receptor deficiency.