Co-treatment with VS and ABT-888 significantly inhibits tumor growth and improves the survival of NOD/SCID mice bearing MDA-MB-231 xenografts A. Mean tumor volume of mice treated with vehicle, ABT-888 and/or VS for 3 weeks. Mice treated with ABT-888 and VS displayed significantly smaller tumors than mice treated with ABT-888 alone (p=0.037) or VS alone (p=0.04). B. Kaplan-Meier survival plot of the mice treated with vehicle, ABT-888, VS, or ABT-888+VS. Mice treated with the combination of ABT-888 and VS demonstrated significantly improved survival (p=0.02) by Log rank (Mantel-Cox) test. C. Representative immunoblots of BRCA1, ATR, CHK1, RAD52, γ-H2AX, cleaved Caspase 3, acetyl histone H3, BIM and β-actin in cell lysates from tumors harvested from mice following 1 week of treatment with ABT-888 and/or VS. D. HCC1937, MDA-MB-231 and SUM159PT cells were treated with cisplatin and vorinostat (VS) for 48 hours and the % apoptotic cells was determined by flow cytometry. Median dose effect and isobologram analyses were performed using Calcusyn. Combination index (CI) values less than 1.0 indicate a synergistic interaction of the two agents in the combination. E. Pan-HDAC inhibitor, by inhibiting HDAC6 levels and activity, induces acetylation and inhibits the chaperone activity of hsp90. This disrupts the chaperone association of hsp90 with its client proteins, such as ATR, BRCA1, RAD52 and CHK1, leading to depletion of their expression levels. Cisplatin treatment leads to decreases in DNA repair and abrogation of cell cycle checkpoints. Treatment with PARP inhibitor inhibits DNA repair leading to accumulation of DNA damage. Combined treatment with HDAC inhibitor and PARP inhibitor leads to greater DNA damage and increased cell death through increased ROS and inhibition of homologous recombination due to depletion of BRCA1 and RAD52. Combined treatment with pan HDAC inhibitor and cisplatin causes greater abrogation of cell cycle checkpoints through HDAC inhibitor-mediated depletion of ATR and CHK1. In addition, accumulation of DNA damage from the combined action of HDAC inhibitor and cisplatin leads to increased cell death of breast cancer cells.