Brother of the regulator of imprinted sites (BORIS) is an epigenetically acting transcription factor which represses the tumor inhibitor functions of the tumor suppressor protein CTCF. BORIS expression has not been documented in adult females, making it an exciting molecular target for drug development in breast cancer. Previously, we demonstrated that vaccination of mice with zing-finger (ZF)-deleted non-functional BORIS results in regression of breast cancer and generation of potent anti-tumor immune responses. RNAi induction can be used as an alternative approach for selective tumor cell killing. Short interfering RNA (siRNA) molecules targeting BORIS were generated and their efficacy was tested in MDA-MB-231 breast cancer and non-malignant epithelial cell lines. Treatment with BORIS-specific siRNA, but not control siRNA led to a concentration-dependent reduction in BORIS expression and proportional apoptotic death of the cancer but not control cells. To our knowledge this is first report demonstrating a critical role of BORIS in maintaining tumor cell viability.