Secondly, insulin receptor, insulin-like growth factor 1 receptor ( IGF-1R) and HER2 all belong to the tyrosine kinase receptor superfamily, insulin could directly or indirectly activated the IR/IGF-1R/HER2 signaling pathway [44, 45], promoting the growth and metastasis of BC cells, contributing to trastuzumab resistance and trastuzumab-induced cardiotoxicity in HER2-positive BC patients [46, 47]. This evidence concerns the gene INSR and breast cancer.