It has been estimated that expression of at least 30% of mammalian protein-encoding genes is regulated, to some extent, by microRNAs (miRNAs) via the RNAi pathway. We have used our expertise and knowledge, based on exploitation of the RNAi mechanism, to develop research focused on the regulation of normal- and cancer-associated gene expression by miRNAs. MicroRNAs are expressed as primary miRNA transcripts that undergo multi-step enzymatic processing to generate the mature form via a precursor intermediate. miRNAs exert their effect on endogenous gene expression through the formation of a ribonucleoprotein complex that uses the miRNA as a guide for the alignment of the complex with a transcript. Determination of the molecular mechanism(s) by which miRNAs modulate protein expression is the subject of intense study. As yet no consensus model has emerged to explain all the proposed facets of miRNA-mediated gene regulation. Although miRNA-induced cleavage and degradation of a target mRNA has been reported, translational repression is currently the favored model of miRNA-mediated gene silencing in mammalian cells. A variety of biological processes have been implicated as being regulated by miRNAs, including cell development, differentiation, proliferation, and metabolism. The involvement of miRNAs in human disease has been particularly focused in cancer biology. Our research studies are focused on the hypothesis that the regulation of gene expression by miRNAs is altered in cancer. We have recently identified miRNAs within a region associated with genomic instability adjacent to MYC and, we and others, have shown that at least two of these miRNAs, miR-1204 and miR-1206, may be functionally active. Current research is focused on examining the over expression of one of these miRNAs miR-1204 in a mouse model of cancer to determine whether this miRNA has a possible functional role in B cell lymphomagenesis. We have over-expressed either miR-1204 or miR-1206 in normal prostate cells in an attempt to reconstitute the over-expression and amplification of genes found in the 8q24 region in many epithelial malignancies including prostate, breast colon and pancreatic carcinoma. We are also interested in further analyzing the overall genomic distribution of miRNAs in relationship to known markers of genomic instability particularly retroviral integration sites associated with mouse models of cancer and understanding the effect sequence variation may play in altering the expression or processing of miRNAs and related regulatory RNAs. Finally, in 2011 we completed a study establishing the receptor tyrosine kinase AXL as a functionally relevant target of miR-34a in breast cancer.