The development of drug resistance is particularly relevant in breast cancer, where dysregulated IRS-1/IGF-1R signaling decreases the sensitivity to tamoxifen and trastuzumab in estrogen receptor (ER)- and HER2-positive tumors, respectively, by potentiating ERK and PI3K/Akt signaling (63, 65, 66). This evidence concerns the gene ESR1 and breast cancer.