Abstract
<div>Abstract<p>HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2<sup>+</sup> breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2<sup>+</sup> breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)–deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2<sup>+</sup> trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival <i>in vitro</i> and tumor growth <i>in vivo</i> of HER2<sup>+</sup> TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-κB–regulated genes. In particular, silencing PARP-1 inhibited NF-κB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2<sup>+</sup> breast cancer cells and support the testing of PARPi in patients with HER2<sup>+</sup> breast cancer resistant to trastuzumab. <i>Mol Cancer Ther; 17(5); 921–30. ©2018 AACR</i>.</p></div>
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