UHRF1, also known as ICBP90 (inverted CCAAT box binding protein 90) in human, is a nuclear protein that acts as a fundamental regulator in cell proliferation and maintains DNA methylation. It is reported that UHRF1 is obviously upregulated in various human malignancies, but unchanged in differentiated tissues, suggesting that UHRF1 plays a crucial role in carcinogenesis and can be a useful anticancer drug target. In this study, we explored whether UHRF1 can be a therapeutic target for human breast carcinoma. We successfully constructed the tumor-specific shRNA expression vector driven by survivin promoter targeting UHRF1 gene. The tumor-specific RNA interference system efficiently and specifically knocked down UHRF1 expression, induced the apoptosis of tumor cells, and enhanced chemosensitivity of tumor cells to cisplatinum, but not in normal cells in vitro and in vivo. Therefore, the survivin promoter-driving shRNA expression system targeting UHRF1 may play a vital and potential role for the treatment of specificity and high efficacy in human breast carcinomas.