MiR-1976 knockdown promotes epithelial–mesenchymal transition and cancer stem cell properties inducing triple-negative breast cancer metastasis

Abstract

AbstractTriple-negative breast cancer (TNBC), characterized by high aggression and invasiveness, has a worse prognosis than other subtypes of breast cancer. Establishing a novel animal model is helpful to understand the mechanisms involved in the progress of TNBC metastasis. In a self-established mouse model consisting normal human breast tissues and normal human bone tissues, TNBC cell line SUM-1315 could spontaneously form species-specific bone metastasis. The expression level of miR-1976 in SUM-1315-bo (derived from metastatic bone tumor) was found lower than that in SUM-1315-br (derived from orthotopic breast tumor). MiR-1976 was found to be downregulated in TNBC tissues, and lower expression of miR-1976 was correlated with worse overall survival in a patient cohort obtained from TCGA database. MiR-1976 knockdown promoted epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties in vitro and in vivo. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) was verified as a target gene by sequencing, biotinylated miRNA pull-down, and luciferase reporter assay. Moreover, overexpression and suppression analysis implicated PIK3CG as a mediator of the biological effects of miR-1976. Our study demonstrated that miR-1976 knockdown could promote EMT and CSCs by PIK3CG. These findings may reveal mechanisms of TNBC metastasis, and represent a potential treatment target for patients with TNBC.