Integrin α5 down-regulation by miR-205 suppresses triple negative breast cancer stemness and metastasis by inhibiting the Src/Vav2/Rac1 pathway

Triple negative breast cancer (TNBC) usually displays more aggressive metastasis, the underlying mechanism is unclear. Previous studies showed that microRNA-205 (miR-205) has controversial roles in cancer, however, its role in TNBC metastasis and the underlying mechanism have not been well-understood. In this study we found that miR-205 expression level is extremely low in basal mesenchymal-like highly migratory and invasive TNBC cells. Stably re-expressing miR-205 in TNBC cells significantly reduced their migration, invasion capability and cancer stem cell (CSC)-like property. Nude mouse orthotopic mammary xenograft tumor model study revealed that miR-205 re-expression greatly decreases TNBC tumor growth and abolishes spontaneous lung metastasis. Mechanistic studies demonstrated that miR-205 inhibits TNBC cell metastatic traits and tumor metastasis by down-regulating integrin α5 (ITGA5). Moreover, ITGA5 knockout using the CRISPR/Cas9 technique achieved the same strong inhibitory effect on TNBC cell CSC-like property and tumor metastasis as re-expressing miR-205 did. Further mechanistic studies indicated that ITGA5 down-regulation by miR-205 re-expression impairs TNBC cell metastatic traits by inhibiting the Src/Vav2/Rac1 pathway. Together, our findings suggest that miR-205 and ITGA5 may serve as potential targets for developing effective therapies for metastatic TNBC.