Abstract B34: Inhibition of breast cancer cell metastasis with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFbeta/miR-21 signaling

Abstract

Abstract Compelling efficacy on intervention of tumor occurrence and progression by nonsteroidal anti-inflammatory drugs (NSAIDs) has been intensively reported in numerous preclinical and clinical studies. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID, sulindac sulfide (SS), referred as sulindac sulfide amide (SSA) was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of variable cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results showed that SSA could inhibit breast tumor cell invasion and migration at sub-cytotoxic concentrations; whereas we previously reported that SS has similar activity on breast and colon tumor cells but at a concentration (50 µM) over 10 times higher than SSA (4 µM). We found that miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, could be downregulated by SSA and involved in mediation of anti-invasive activity of SSA in breast tumor cells. When studying the mechanisms responsible for the regulation of miR-21 by SSA, we demonstrated that TGFbeta signaling suppressed by SSA could ultimately result in downregulation of miR-21 through the transcriptional control. Reduction of Smad2 and Smad3 phosphorylation was the direct response to SSA treatment in metastatic breast tumor MDA-MB-231 cells. By using ChIP assay, we demonstrated that phosphorylated Smad2/3 could bind to the promoter of miR-21 gene. Therefore, in this project, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis through a new mechanism involving the TGFbeta/miR-21 signaling axis. This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC). Citation Format: Bin Yi, Hong Chang, Xiangling Feng, Ruixia Ma, Gary A Piazza, Yaguang Xi. Inhibition of breast cancer cell metastasis with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFbeta/miR-21 signaling. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B34.