Tankyrases (TNKS1 and TNKS2) are members of the human poly(ADP-ribose) polymerase (PARP) family and catalyze PARsylation by using NAD+ as a substrate to modify various proteins in order to regulate various cellular processes including Wnt/β-catenin signaling. TNKS1 has been shown to be overexpressed and to be correlated with highly aggressive disease and prognosis in various types of human cancers. A small molecule inhibitor of TNKS1, XAV-939 has been proven to be a potent inhibitor of Wnt/β-catenin signaling by stabilizing Axin. However, the effect of tankyrase inhibitors as potential breast cancer therapy is still under investigation. In this study, we found that TNKS1 is highly expressed in breast cancer cell lines, particularly in triple-negative breast cancer (TNBC) cells and that the expression of TNKS1 correlates with anti-proliferative efficacy of tankyrase inhibitors, XAV-939 and JW55. Also, XAV-939 treatment suppressed cell migration and invasion capabilities and epithelial-mesenchymal transition (EMT) signaling in triple-negative breast cancer cell lines. Moreover, XAV-939 reduced expression of stemness markers. It was shown that polo-like kinase 1 (PLK1) functions as a positive regulator of TNKS1 protein stability. Interestingly, we found that combination treatment of XAV-939 with PLK inhibitor GW843682X significantly suppressed cell growth, clonogenic potential, migratory and invasive capabilities of breast cancer cells. The combination of XAV-939 with ionizing radiation (IR) also showed an additional therapeutic effect. Therefore, our findings highlight the important value of TNKS1 as a therapeutic target and suggest the potential for improving the clinical efficacies of tankyrase inhibitors in combination with either PLK inhibitors or radiotherapy for patients with triple-negative breast cancer.
Citation Format: Maya Mathew, Loredana Campo, Jung-Lye Kim, Geun-Hyoung Ha, Eun-Kyoung Breuer. Targeting tankyrases as a therapeutic strategy for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1119. doi:10.1158/1538-7445.AM2017-1119