In summary, our studies provide the first evidence that a subgroup of GPCRs, Gi/o-GPCRs, is critical for CSC function in HER2+ breast cancer and that targeting signaling by Gi/o-GPCRs through PI3K/AKT and Src pathways enhances HER2-targeted therapy for eradicating CSCs. This evidence concerns the gene ERBB2 and breast cancer.