Using trastuzumab and high-HER2-expressing breast cancer cells, this study provided for the first time in vitro and in vivo experimental evidence that proteinase cleavage of trastuzumab at the lower hinge compromised its Fc-mediated immune effector functions such as ADCC in vitro, which resulted in reduced anti-tumor efficacy in vivo. The gene discussed is ERBB2; the disease is breast cancer.