Currently, the molecular mechanisms that explain HER2 suppression by trastuzumab remain unclear, with various hypotheses proposed. Despite these beneficial outcomes, resistance to trastuzumab is common, and can occur early in the treatment regime. Trastuzumab treatment leads to reduced HER2 signaling, reduced tumor angiogenesis, cell cycle arrest, and enhanced anti-tumor immune responses. The monoclonal antibody trastuzumab (Herceptin™) has proven to be an effective adjuvant therapy against HER2+ breast cancers. The human epidermal growth factor receptor-2 (HER2)-positive (HER2+) subtype, characterized by overexpression of HER2 receptor, accounts for 20% of cases and has high rates of metastasis. This classification has revealed different rates of breast cancer metastasis based on molecular subtype. Gene expression profiling has identified four main subtypes of breast cancer that differ in driver genes and optimal therapies. This progression involves the acquisition of adaptive changes within tumor cells and the tumor microenvironment. Mortality in patients with breast cancer is primarily due to the development of metastatic disease. Thus, differential expression of Endo II may relate to sensitivity or resistance to trastuzumab-based therapies for HER2+ cancers. Our study provides novel evidence of Endo II function in HER2+ cancer cell motility and trafficking of HER2 that relates to effective treatments with trastuzumab or T-DM1. In addition, Endo II silencing also impaired HER2 internalization in response to Trastuzumab, and led to reduced cytotoxicity response in HER2+ cancer cells treated with T-DM1. Endo II silencing also led to decreased migration and invasion of HER2+ cancer cells in vitro, and impaired lung seeding following tail vein injection in mice. Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface, impaired epidermal growth factor-induced HER2 internalization, and reduced signaling to downstream effector kinases Akt and Erk. High Endo II protein expression was detected in HER2-positive tumors, and was linked to worse overall survival in node-positive HER2+ breast cancers at the mRNA level. The effects of Endo II silencing on the responses of HER2+ cancer cells to trastuzumab or T-DM1 treatments were tested using real-time cell motility and cytotoxicity assays. Stable silencing of Endo II was achieved in HER2+ cancer cell lines (SK-BR-3 and HCC1954) to test Endo II effects on HER2 levels, localization and signaling, cell motility and tumor metastasis. MethodsĮndo II expression in human breast tumors and lymph node metastases were analyzed by immunohistochemistry. Here, we test the involvement of the endocytic adaptor protein endophilin A2 (Endo II) in HER2+ breast cancer models, and their responses to treatments with trastuzumab and T-DM1. However, resistance to these targeted therapies can develop and limit their efficacy. Targeted therapies involving the antibody trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2-positive (HER2+) breast cancer patients. Human epidermal growth factor receptor-2 (HER2) is amplified and a clinical target in a subset of human breast cancers with high rates of metastasis.
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