A phase II, single arm, ‘window of opportunity’ neoadjuvant metformin clinical study (NCT00897884, phase II, Table 2) conducted in non-diabetic early stage breast cancer patients investigated whether taking metformin (500 mg; thrice daily for ≥ 2 weeks after diagnostic biopsy) until surgery could reduce cell proliferation rates in the tumor tissue and reported reduced levels of phosphorylated Akt and ERK1/2, coupled to reduction on the levels of insulin and insulin receptors indicating that the anti-cancer effect of metformin presents insulin-dependent effects in a clinical scenario [136]. Here, INS is linked to breast carcinoma.