MicroRNA-Mediated Mitochondrial Dysfunction Is Involved in the Anti-triple-Negative Breast Cancer Cell Activity of Phytosesquiterpene Lactones.

Aims: Emerging evidence suggests that modulating redox homeostasis through targeting mitochondrial functions may be a useful strategy for suppressing triple-negative breast cancer (TNBC) activities. However, whether there are specific microRNAs (miRNAs) involved in regulating oxidative stress-associated mitochondrial functions that can act as therapeutic targets to suppress TNBC activities remains unclear. Here, we aimed to identify the role of redox-associated miRNAs in TNBC and investigated their potential as therapeutic targets. Results: We identified oxidative stress-responsive differentially expressed miRNAs (DEMs) regulated by phytosesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35, which are known to inhibit TNBC growth and metastasis in vitro and in vivo , using comparative miRNA microarray analysis and reactive oxygen species (ROS) scavenging approaches. Mitochondrial dysfunction was identified as a major biological function regulated by a few specific DEMs. In particular, miR-4284 was identified to play a role in DET- and DETD-35-mediated ROS production, mitochondrial basal proton leak, and antiproliferation activity in TNBC cells. Moreover, DET- and DETD-35-induced mitochondrial DNA damage was observed in TNBC cells and xenograft tumors. miR-4284 was also identified to play a role in oxidative DNA damage in TNBC tumors. Innovation: We identified a novel role for miR-4284 in regulating mitochondrial basal proton leak in TNBC cells, and highlighted its significance in TNBC tumor oxidative DNA damage, and its direct correlation with TNBC patient survival. Conclusion: We used DET and DETD-35 as proof of concept to demonstrate that activities of anticancer agents can involve regulation of multiple miRNAs playing different roles in cancer progression.