ERBB2 and breast cancer: Mechanisms of drug resistance in HER-2+ breast cancer include inadequate blockade of the HER-2 receptor, activation of downstream signaling pathways like PI3K and MAPK, inhibition of tumor suppressor genes, acquired HER-2 mutations, dysregulation of cell cycle regulators (high copy number of the CCND1 gene encoding cyclin D1), and non-cell autonomous mechanisms within the tumor microenvironment (Kay et al., 2021; Choong et al., 2020; Zhang, 2021).