The stromal loss of miR-4516 promotes the FOSL1-dependent proliferation and malignancy of triple negative breast cancer.

Stroma-derived exosomal microRNA (exomiR) contributes to tumor progression, however, which remains poorly understood. In our study, we analyzed exomiRs from the cancer-associated fibroblast (CAF) and normal fibroblast (NF) isolated from an invasive ductal carcinoma (IDC) patient and found that the level of microRNA (miR)-4516 was approximately 5-fold lower in CAF-derived exosomes than NF-derived ones. In gene annotation analysis, miR-4516 target genes were mainly associated with the regulation of proliferation. miR-4516 overexpression or mimic treatment suppressed the proliferation of breast cancer cells, especially triple negative breast cancer (TNBC) cells. Among miR-4516 targets, FOSL1 was overexpressed in TNBC cells compared to non-TNBC cells and promoted tumor proliferation. The expression of miR-4516 and FOSL1 was reversely correlated in breast cancer patient tissues. Particularly, TNBC patients with high FOSL1 expression showed a significant poorer survival than those with low FOSL1 expression. Our results show that the loss of miR-4516 from CAF-derived exosomes is associated with FOSL1-dependent TNBC progression and suggest that miR-4516 can be used as an anti-cancer drug for TNBC.