TY - JOUR
T1 - Trastuzumab-resistant HER2 þ breast cancer cells retain sensitivity to poly (adp-ribose) polymerase (parp) inhibition
AU - Wielgos, Monica E.
AU - Zhang, Zhuo
AU - Rajbhandari, Rajani
AU - Cooper, Tiffiny S.
AU - Zeng, Ling
AU - Forero, Andres
AU - Esteva, Francisco J.
AU - Kent Osborne, C.
AU - Schiff, Rachel
AU - LoBuglio, Albert F.
AU - Nozell, Susan E.
AU - Yang, Eddy S.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/5
Y1 - 2018/5
N2 - HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 þ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 þ 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 þ 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 in vitro and tumor growth in vivo of HER2 þ 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-kB–regulated genes. In particular, silencing PARP-1 inhibited NF-kB 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 þ breast cancer cells and support the testing of PARPi in patients with HER2 þ breast cancer resistant to trastuzumab.
AB - HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 þ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 þ 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 þ 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 in vitro and tumor growth in vivo of HER2 þ 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-kB–regulated genes. In particular, silencing PARP-1 inhibited NF-kB 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 þ breast cancer cells and support the testing of PARPi in patients with HER2 þ breast cancer resistant to trastuzumab.
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U2 - 10.1158/1535-7163.MCT-17-0302
DO - 10.1158/1535-7163.MCT-17-0302
M3 - Article
C2 - 29592880
AN - SCOPUS:85047799288
SN - 1535-7163
VL - 17
SP - 921
EP - 930
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -