However, in premenopausal patients this is an unlikely mechanism because not only is most of the circulating estrogen produced in the ovaries, but the majority of the tumors are estrogen independent, and obesity-related stimulation of breast cancer growth, invasion, and metastasis is derived from non-steroidal factors, including proinflammatory cytokines, leptin, eicosanoids, and insulin [51]. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.