Breast cancer cells can develop metformin resistance by triggering IGF-1R target insulin receptor substrate-1 (IRS-1)/ERK signaling through overactivation of FGFR1; IRS-1 acts as a critical crosstalk mediator between IGF-1R and FGFR1 pathways, encompassing a feedback loop between IRS-1 and MAPK/ERK (3). The gene discussed is IRS1; the disease is breast carcinoma.