Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition
| Autor: | Rachel Schiff, Francisco J. Esteva, Eddy S. Yang, Albert F. LoBuglio, Monica E. Wielgos, Andres Forero, Zhuo Zhang, C. Kent Osborne, Susan Nozell, Ling Zeng, Tiffiny S. Cooper, Rajani Rajbhandari |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Veliparib Cell Survival Receptor ErbB-2 Poly ADP ribose polymerase Mice Nude Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer Antineoplastic Agents Immunological Trastuzumab Cell Line Tumor medicine Gene silencing Animals Humans Cytotoxicity skin and connective tissue diseases neoplasms Mice Inbred BALB C Chemistry Cancer medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Oncology Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Benzimidazoles Female medicine.drug |
| Popis: | HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ 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+ 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+ 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+ breast cancer cells and support the testing of PARPi in patients with HER2+ breast cancer resistant to trastuzumab. Mol Cancer Ther; 17(5); 921–30. ©2018 AACR. |
| Databáze: | OpenAIRE |
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