Abstract MicroRNAs (miRNAs) regulate important developmental events and are often misexpressed in human cancers, but little is known regarding how these small RNAs contribute to tumor formation. Our laboratory uses a combination of nematode and mammalian model systems to functionally characterize miRNAs and determine the role these factors play in controlling cancer progression pathways. We have successfully used the nematode to analyze how members of the lin-4 and let-7 miRNA families functionally overlap to direct common developmental events associated with cell cycle progression and differentiation. Specifically, animals that carry a triple deletion for the lin-4 homologue, mir-237, and the let-7 homologues, mir-48 and mir-84, exhibit morphological defects and fertility problems related to abnormal mitotic and meiotic abnormalities in the germline that were not found in the single or double deletion combinations. We have also begun to determine how the let-7 miRNA family functions as tumor suppressor genes in mammals. Our experiments showing that exogenous let-7 miRNA administration in the lung using a conditionally activated KRAS lung cancer mouse model result in reduced lung tumor load in these animals highlight the therapeutic potential of miRNAs. We are also studying the role of let-7 together with other miRNA families in directing cancer progression pathways in human tissues of urothelial origin. For instance, we find that let-7 is dysregulated in human prostate cancer cell lines differing in their metastatic status and indicates a novel role for this miRNA in prostate cancer progression. Due to our access to a vast repository of human prostate specimens from the Virginia Prostate Center at Eastern Virginia Medical School, we have begun to analyze the miRNA expression profiles in FFPE specimens taken from the primary prostate tumor, normal adjacent tissue and the lymph node metastasis of individual prostate cancer patients as well as in tumors from patients presenting insignificant and organ confined cancer. We are also determining the “miRNA signatures” in blood, urine, and expressed prostatic secretions (EPS) that were obtained non-invasively from both normal and cancer patients. Our work investigating the role of miRNAs during cancer progression promises to reveal novel therapeutic approaches and diagnostic and prognostic biomarkers for human cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 LB-353.