Increased Expression of MicroRNA 551a by c-Fos Reduces Focal Adhesion Kinase Levels and Blocks Tumorigenesis

ABSTRACT

Breast cancer is a recurrent type of cancer among women worldwide. Despite remarkable progress in the prevention, detection, and treatment of breast cancer, it still remains a major chronic problem worldwide and poses significant challenges, like metastasis to distant organs, demanding the need for novel biomarkers and therapeutic targets. Focal adhesion kinase (FAK), a member of the protein tyrosine kinases, has been shown to be expressed in high levels in breast tumors. Of late, FAK has emerged as an impending curative target in breast carcinoma, with few of the small molecular inhibitors reaching the clinical trial stage. In the current study, we established that microRNA 551a (miR-551a) precisely regulates FAK by binding to the complementary sequences in the 3′ untranslated region (UTR) of mRNAs of FAK and inhibits its expression in breast carcinoma cell lines. Further, results from human breast carcinoma samples illustrated that miR-551a levels were substantially downregulated in tumor samples, with a concurrent rise in the expression of FAK. Functional experimental studies using miR-551a-overexpressing breast cancer cells and nude mouse xenograft models revealed the tumor suppressor role of miR-551a. We also found that miR-551a expression decreased the invasion and migratory ability of breast carcinoma cells by inhibiting MMP-9 activity. Regulation studies performed utilizing promoter luciferase assays, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) revealed that c-Fos binds to the miR-551a promoter and activates it. Further, we observed a considerable increase in the amount of miR-551a levels upon c-Fos overexpression. All of these results showed that miR-551a can be of clinical relevance in understanding the regulation of FAK in breast tumorigenesis.