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DNA flap endonuclease 1(FEN1) plays critical roles inmaintaining genomestability and integrity by participating in both DNA replication and repair.Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates,resulting in DNA double strand breaks(DSBs) and apoptosis.Therefore,targeting FEN1 could serve as a potent strategy for cancer therapy.In this study,we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells.We showed thatmanipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs.Furthermore,we identified a small molecular compound,SC13 that specifically inhibits FEN1 activity,thereby interfering with DNA replication and repair in vitro and in cells.SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells.Importantly,SC13 sensitizes cancer cells to DNA damage-inducing therapeuticmodalities and impedes cancer progression in amouse model.These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.