Abstract
A recent report identified six microRNAs with repressed expression in highly metastatic MDA-MB-231 breast cancer cell derivatives (miRs 335, 126, 206, 122a, 199a*, and 489). Expression of all six miRs was consistently decreased in cells that produced aggressive lung and bone metastases, as compared to parental cells, indicating that metastatic colonization is exacerbated by the concurrent loss of multiple miRs from this set. With the hypothesis that target genes involved in metastatic progression are regulated by cooperative activity of these six microRNAs, we performed a computational analysis to identify transcripts having multiple binding sites targeted by the collective set of miRs. Using miR-AT!, a new web-based computational tool developed in our laboratory, we identified 767 target transcripts with multiple sites, and we characterized the biological processes and pathways associated with the target genes. Among cellular processes enriched with genes from this set are regulation of cell cycle, cytoskeleton organization, and regulation of cell adhesion. Importantly, perturbation of these processes was recently noted as a common feature among all metastatic tumors. We have identified subsets of the six miRs that are predicted to regulate the genes in each of these critical cellular processes. Additionally, we analyzed signaling pathways downstream of the collective set of target genes to identify key regulatory molecules where the networks converge. The top scoring nodes were cyclin D1 and c-myc, suggesting that dysregulation of target genes due to the collective loss of the microRNAs may have a focused effect on the activity of these two key genes. Access to miR-AT! is available at www.mir-at.org. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2069.