Downregulation of Rab27A contributes to metformin-induced suppression of breast cancer stem cells.

Cancer stem cells (CSCs) are associated with tumor initiation, therapeutic resistance, relapse and metastasis. However, the underlying mechanisms CSCs use to preserve stemness are not yet fully understood. The present study demonstrated that the expression of RAB27A, member RAS oncogene family (Rab27a), which was reported to promote tumor progression by upregulating exocytosis of extracellular vesicles, was higher in mammosphere cells than in adherent MDA-MB-231 breast cancer cells. Downregulation of Rab27A inhibited mammosphere formation by decreasing the proportion of CD44+CD24-/low cells of the MDA-MB-231 cell line. Furthermore, Rab27A overexpression redistributed the cell cycle of breast (b) CSCs. The present study revealed that downregulation of Rab27A enhanced the capacity of metformin, the most widely used oral hypoglycemic drug for the treatment of type II diabetes, to inhibit mammosphere growth. Metformin reduced the expression of Rab27A dose-dependently. These data suggested that Rab27A acts as a mediator of human bCSCs by promoting the growth of mammospheres and that synergistic suppression of Rab27A, alone or in combination with metformin, holds promise for therapeutically targeting bCSCs.