Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. Recently, we showed KLK5 reconstitution in breast cancer cell lines suppresses malignancy. Present study aims to investigate the functional KLK5 mediated miRNA network on breast cancer progression, molecular subtype and survival. 28 miRNAs were up-regulated and 62 miRNAs were down-regulated upon KLK5 expression. Extracellular matrix (ECM) molecules and cell-adhesion pathways were the most significant KLK5-induced miRNA-mediated regulatory targets. Validation from The Cancer Genome Atlas (TCGA) database indicated KLK5 was specifically down-regulated in luminal B and basal-like breast cancer subtypes. There was a correlation between KLK5, miRNAs and their downstream ECM gene targets. Long-term patient survival correlated with dysregulation of KLK5 and interacting ECM target genes. It suggests biological differences between breast cancer molecular subtypes, patient survival, and their propensity for invasion and metastasis can be explained in part by altered miRNA networks induced by KLK5 dysregulation. We provide the first evidence that KLK5 can affect miRNA networks, which regulate MMPs and other novel ECM targets and a new compelling hypothesis of interplay between serine proteases and miRNAs. We developed a combined KLK5-(ITGB1+COL12A1) predictive score for recurrence-free survival that could be exploited in clinical applications.