Upregulation of miR-374a promotes tumor metastasis and progression by downregulating LACTB and predicts unfavorable prognosis in breast cancer

Cancer Med. 2018 May 23;7(7):3351-3362. doi: 10.1002/cam4.1576. Online ahead of print.

Abstract

Breast cancer (BRCA) is the second leading cause of cancer-related death among female worldwide. Recent studies have revealed that LACTB was frequently repressed and functioned as a bona fide new tumor suppressor in a series of cancers, including BRCA. However, the molecular mechanisms underlying LACTB dysregulation in BRCA have not been reported. In the present study, we find that LACTB is repressed in BRCA and associated with poor prognosis by BRCA tissue microarray (TMA) analysis. Moreover, we confirm that LACTB is a direct target of miR-374a, which is significantly overexpressed and associated with malignancies in BRCA. Mechanistically, applying loss-of-function and gain-of-function approaches in a series of in vitro and in vivo experiments show that miR-374a knockdown suppresses the cell proliferative and colony formation activity, as well as migration and invasion capacity, but LACTB silencing in these cells reverses this change. Furthermore, we find that miR-374a silencing markedly reduces the tumor growth in xenograft mouse models. In summary, our findings suggest the miR-374a/LACTB axis plays a critical role in the tumorigenicity and progression of BRCA. miR-374a/LACTB axis may be a potential target in the development of therapeutic strategies for BRCA patients.

Keywords: LACTB; breast cancer; metastasis; miR-374a; proliferation.