Pterostilbene, a bioactive component of blueberries, suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via modulating NF-κB/microRNA 448 circuit

Scope Tumor‐associated macrophages (TAMs) have been shown to promote metastasis and malignancy. Pterostilbene, a natural stilbene isolated from blueberries, has been suggested for anti‐cancer effects. Here, we explored the potential cancer stem cells (CSCs)/TAM modulating effects of pterostilbene in breast cancer. Methods and results Using flowcytometric and Boyden chamber assay, we showed MCF7 and MDA‐MB‐231 cells cocultured with M2 TAMs exhibited increased percentage of CD44+/CD24− CSC population and migratory/invasive abilities. RT‐PCR results showed that CD44+/CD24− cells expressed an increased level of HIF‐1α, β‐catenin, Twist1, and NF‐κB and enhanced tumor sphere forming ability. Additionally, pterostilbene treatment dose dependently overcame M2 TAM‐induced enrichment of CSCs and metastatic potential of breast cancer cells. Mechanistically, pterostilbene suppressed NFκB, Twist1, vimentin, and increased E‐cadherin expression. Using siRNA technique, we demonstrated that pterostilbene‐mediated NFκB downregulation was correlated to an increased amount of microRNA 448. Finally, pterostilbene‐mediated suppression in tumorigenesis and metastasis was validated by noninvasive bioluminescence in mice bearing M2 TAM cocultured MDA‐MB‐231 tumor. Conclusion Pterostilbene effectively suppresses the generation of CSCs and metastatic potential under the influence of M2 TAMs via modulating EMT associated signaling pathways, specifically NF‐κB/miR488 circuit. Thus, pterostilbene could be an ideal anti‐CSC agent in clinical settings.