Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.

Abstract	There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.
Authors	Kyungsoo Ha, Warren Fiskus, Dong Soon Choi, Srividya Bhaskara, Leandro Cerchietti, Santhana G T Devaraj, Bhavin Shah, Sunil Sharma, Jenny C Chang, Ari M Melnick, Scott Hiebert, Kapil N Bhalla
Journal	Oncotarget (Oncotarget) Vol. 5 Issue 14 Pg. 5637-50 (Jul 30 2014) ISSN: 1949-2553 [Electronic] United States
PMID	25026298 (Publication Type: Journal Article)
Chemical References	BRCA1 Protein BRCA1 protein, human Enzyme Inhibitors HSP90 Heat-Shock Proteins Histone Deacetylase Inhibitors Hydroxamic Acids Indoles Poly(ADP-ribose) Polymerase Inhibitors Reactive Oxygen Species Vorinostat Panobinostat Protein Kinases ATR protein, human Ataxia Telangiectasia Mutated Proteins Checkpoint Kinase 1 Cisplatin
Topics	Animals Antineoplastic Combined Chemotherapy Protocols (pharmacology) Apoptosis (drug effects) Ataxia Telangiectasia Mutated Proteins (metabolism) BRCA1 Protein (genetics, metabolism) Cell Line, Tumor Checkpoint Kinase 1 Cisplatin (administration & dosage, pharmacology) DNA Damage Drug Synergism Enzyme Inhibitors (pharmacology) Female Gene Knockdown Techniques HSP90 Heat-Shock Proteins (metabolism) HeLa Cells Histone Deacetylase Inhibitors (administration & dosage, pharmacology) Humans Hydroxamic Acids (pharmacology) Indoles (pharmacology) MCF-7 Cells Mice Panobinostat Poly(ADP-ribose) Polymerase Inhibitors Protein Kinases (metabolism) Reactive Oxygen Species (metabolism) Triple Negative Breast Neoplasms (drug therapy, genetics) Vorinostat Xenograft Model Antitumor Assays

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