Baldassarre T et al. Targeted therapies with trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2+ breast cancer. In the currebnt study, involvement of Endo II in HER2+ breast cancer and the responses to treatments with trastuzumab and T-DM1 were evaluated.It was shown that Endo II functions in HER2+ cancer cell motility and trafficking of HER2 is related to effective treatment with trastuzumab or T-DM1.

Methods

• Endo II expression in human breast tumors and lymph node metastases were analyzed by immunohistochemistry.
• Endo II stable silencing was achieved in HER2+ cancer cell lines (SK-BR-3 and HCC1954) to test Endo II effects on HER2.
• The effects of Endo II silencing on the responses of HER2+ cancer cells to trastuzumab or T-DM1 treatments were tested.

Results

• 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.
• 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.
• Endo II silencing led to decreased migration and invasion of HER2+ cancer cells in vitro.
• 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.