Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells
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Kyungsoo Ha1, Warren Fiskus2,*, Dong Soon Choi2,*, Srividya Bhaskara3, Leandro Cerchietti4, Santhana G. T. Devaraj2, Bhavin Shah2, Sunil Sharma3, Jenny C. Chang2, Ari M. Melnick4, Scott Hiebert5 and Kapil N. Bhalla2
1 Georgia Regents University, Augusta, GA
2 Houston Methodist Research Institute, Houston, TX
3 Huntsman Cancer Institute, Salt Lake City, UT
4 Weill Cornell Medical College, New York, NY
5 Vanderbilt University, Nashville, TN
* These authors contributed equally to this work
Kapil N. Bhalla, email:
Keywords: HDAC inhibitor, Triple Negative Breast Cancer, PARP inhibitor, BRCAness
Received: May 13, 2014 Accepted: June 29, 2014 Published: June 30, 2014
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.
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