Such a multi-faceted capacity of metformin to target not only HER2 itself but also central mechanisms implicated in refractoriness to HER2-targeted therapies including both the IGF-I/mTOR signaling pathway and the self-renewal/proliferation of tumor-initiating cancer stem cells [26–30] provides strong experimental support to translate these pre-clinical findings into new metformin-based clinical management strategies that may benefit HER2-positive BC patients. This evidence concerns the gene ERBB2 and breast cancer.