In summary, in combination with the results from the trials listed in Table 1, the results of Dowling et al. strongly suggest that metformin exerts a significant part of its anti-tumor effects in breast cancer via the indirect pathway by lowering serum insulin, inhibiting downstream signaling via PI3K/Akt and Ras-MAPK pathways, and leading to decreases in cell proliferation. Here, INS is linked to breast cancer.