MicroRNAs (miRs) are a critical class of small (21–25 nucleotides) non-coding endogenous RNAs implicated in gene expression regulation. We identified miR-23b and miR-27b as miRNAs that are highly upregulated in human breast cancer. We found that engineered knockdown of miR-23b and miR-27b substantially repressed breast cancer growth. Nischarin (NISCH) expression was augmented by knockdown of miR-23b as well as miR-27b. Notably, these miRNAs and Nischarin were inversely expressed in human breast cancers, underscoring their biologic relevance. We demonstrated the clinical relevance of the expression of these miRNAs and showed that high expression of miR-23b and miR-27b correlates with poor outcome in breast cancer. Moreover, intraperitoneally delivered anti-miR-27b restored Nischarin expression and decreased tumor burden in a mouse xenograft model of human mammary tumor. Also we report for the first time that HER2/neu (ERBB2), EGF, and TNFA promote miR-23b/27b expression through the AKT/NF-κB signaling cascade. Nischarin was found to regulate miR-27b/23b expression through a feedback loop mechanism by suppressing NF-κB phosphorylation. Since anti-miR-27b compounds that suppress miR-27b inhibit tumor growth, the anti-miR-27b appears to be a good candidate for the development of new anti-tumor therapies.

Nischarin may be a novel tumor suppressor that limits breast cancer progression by regulating α5 integrin expression and subsequently α5 integrin-, FAK-, and Rac-mediated signaling.