Beyond leptin signaling onto breast cancer and endothelial cells to directly control the VEGF/VEFR signaling axis and other pro-angiogenic pathways, leptin can also induce a pro-angiogenic TME through estrogen-signaling in breast adipocytes and by promoting pro-inflammatory signaling by tissue- (or tumor-) resident macrophages, as shown in Figure 3. This evidence concerns the gene LEP and breast cancer.