We want to develop a novel therapeutic approach for a subtype of aggressive breast cancer known as triple-negative breast cancer (TNBC), which lacks estrogen and progesterone receptors and does not over-express a protein called Her-2. We have learned a lesson from another type of breast cancer (BRCA mutant): in the presence of a drug that inhibits DNA repair (PARP inhibitor), these breast cancer cells often die. We hope to identify the Achilles heel of TNBC by making these cells sensitive to a PARP inhibitor, causing their death. We will discover the Achilles heel using a modern molecular biology technique called shRNA library screen. This technique delivers an inhibitor against every gene in the breast cancer cell population. Through a somewhat complicated method of selection, we will identify a pathway which, when inhibited, markedly enhances the ability of a PARP inhibitor to kill these breast cancers. Knowing the “killing” pathway, we will identify or synthesize a drug that can inhibit the pathway and, when combined with a PARP inhibitor, kills TNBC. Our approach has the potential to identify an entirely new way of treating this devastating cancer.