Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 921-930 |
| Number of pages | 10 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 17 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2018 |
Bibliographical note
Funding Information:F.J. Esteva is a consultant/advisory board member for Genentech. C.K. Osborne is a consultant/advisory board member for AstraZeneca, Genentech, P. Elmer, and Pfizer, has received expert testimony from O'Melveny and Myers. R. Schiff reports receiving a commercial research grant from AstraZeneca. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We would like to thank Vivo Biosciences for their help with the microtumor experiments as well as Enid F. Keyser for her assistance with the apoptosis and cell cycle experiments. The authors would also like to thank Alice Weaver for her help with an experiment. This study was supported by grants from the American Association of Cancer Research/Genentech Career Development Award (12-30-18-YANG) to E.S. Yang), Susan G. Komen Career Catalyst Award (CCR12364491, to E.S. Yang), Breast Cancer Research Foundation of Alabama (to E.S. Yang), and the Breast SPORE (5P50CA089019 to E.S. Yang) from the University of Alabama-Birmingham Comprehensive Cancer Center. The UAB Comprehensive Flow Cytometry Core Facility is supported by Grants P30 AR048311 and Grant P30 AI027767.
Funding Information:
We would like to thank Vivo Biosciences for their help with the microtumor experiments as well as Enid F. Keyser for her assistance with the apoptosis and cell cycle experiments. The authors would also like to thank Alice Weaver for her help with an experiment. This study was supported by grants from the American Association of Cancer Research/Genentech Career Development Award (12-30-18-YANG) to E.S. Yang), Susan G. Komen Career Catalyst Award (CCR12364491, to E.S. Yang), Breast Cancer Research Foundation of Alabama (to E.S. Yang), and the Breast SPORE (5P50CA089019 to E.S. Yang) from the University of Alabama-Birmingham Comprehensive Cancer Center. The UAB
Publisher Copyright:
© 2018 American Association for Cancer Research.
ASJC Scopus subject areas
- Oncology
- Cancer Research
