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

Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, Shah B, Sharma S, Chang JC, Melnick AM, Hiebert S, Bhalla KN
Oncotarget. 2014 5 (14): 5637-50

PMID: 25026298 · PMCID: PMC4170637 · DOI:10.18632/oncotarget.2154

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.

MeSH Terms (28)

Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis Ataxia Telangiectasia Mutated Proteins BRCA1 Protein Cell Line, Tumor Checkpoint Kinase 1 Cisplatin DNA Damage Drug Synergism Enzyme Inhibitors Female Gene Knockdown Techniques HeLa Cells Histone Deacetylase Inhibitors HSP90 Heat-Shock Proteins Humans Hydroxamic Acids Indoles MCF-7 Cells Mice Panobinostat Poly(ADP-ribose) Polymerase Inhibitors Protein Kinases Reactive Oxygen Species Triple Negative Breast Neoplasms Vorinostat Xenograft Model Antitumor Assays

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