Dual inhibition of ABCE1 and LCP1 by microRNA-96 results in an additive effect in breast cancer mouse model

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that regulate the expression of target genes at the post-transcriptional level. Each miRNA can modulate multiple genes and, as a result, a single miRNA may have a profound effect on a specific biological pathway consisting of several of its target genes. Recent studies have indicated that specific miRNA signatures are correlated with tumor aggressiveness and clinical outcome in breast cancer. We previously demonstrated that miR-96 has a suppressive effect on breast cancer aggressiveness and that this effect was mediated by ABCE1 gene regulation. In this study we investigated whether other miR-96 regulated genes can enhance ABCE1’s anti-cancer effects. We identified one such gene – LCP1 – and proved its negative effect on breast cancer progression. Interestingly, dual inhibition of ABCE1 and LCP1 resulted in an additive effect on cancer cell migration, invasion, and proliferation. Furthermore, in vivo analysis of dual ABCE1 and LCP1 knockdown resulted in significant tumor growth inhibition, decreased metastatic activity, and contributed to survival compared to either gene, separately. This indicates that the combined downregulation of two miR-96 gene targets has an additive effect on reducing cancer aggressiveness. Overall, our work supports seeking more than one target in miRNA-based studies in order to enhance functional effects and better characterize the miRNA wide-spread activity.