The triple negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with poly-ADP-ribose-polymerase (PARP) inhibition in breast cancer cells which harbour silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACis) are a class of drugs, which mediate epigenetic changes in expression of HR pathway genes. Here we compare the activity of the pan-HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA) and the HDAC1/2 specific inhibitor, romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that the two of HDACis tested SAHA and ROMI but not VPA indeed inhibit HR repair and that RAD51, BARD1 and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared to mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting.
- Received May 7, 2015.
- Revision received July 21, 2015.
- Accepted August 3, 2015.
- Copyright © 2015, American Association for Cancer Research.