Collectively, our results disclose two LINC00589-initiated ceRNA networks, the LINC00589-miR-100-DLG5 and LINC00589-miR-452-PRDM16- mucin4 axes, which regulate trastuzumab resistance, CSC-like properties and multiple chemoresistance of breast cancer, thus providing potential diagnostic and prognostic markers and therapeutic targets for HER2-positive breast cancer. The gene discussed is ERBB2; the disease is breast cancer.