Gene expression studies of tumor:normal tissue pairs often reveal lower levels of miRNA in the tumor samples (6) . Various mechanisms for downregulation of miRNA expression have been proposed, including mutations in miRNA genes, epigenetic regulation, and alterations in miRNA pathways mediated by transcription factors.
Initial evidence suggested that many miRNA genes are located at cancer-specific translocation sites, CpG islands, and fragile sites within the genome (7); however, the relationship between deactivation of miRNA genes and oncogenesis is complex and varies depending on the type of cancer (8). Single-nucleotide polymorphisms (SNPs) have been identified in both miRNA genes and their targets, playing opposing roles: some enhance the tumor-suppressor function of the miRNA, while others result in increased miRNA expression and consequent oncogenic activity (9). Further, mutations in the genes encoding miRNA-processing transcription factors Drosha and Dicer1 also resulted in increased tumorigenic activity (10, 11) .
Epigenetic alterations have long been a hallmark of many types of cancer (12). Silencing of miRNA genes by hypermethylation has been observed in breast cancer and colorectal cancer (13) (14) , while the expression of oncogenic miRNAs was increased by DNA hypomethylation in ovarian cancer (15) . Mapping studies have shown that miRNA silencing by methylation of miRNA promoter regions is associated with breast cancer development and metastasis (16). In addition to DNA methylation, altered histone acetylation has been identified to play a role in reducing the expression of antioncogenic miRNAs in breast cancer cells (17) .
A host of transcription factors are involved in expression, processing, and transcription of miRNAs. The oncogenic transcription factor Myc binds to the promoter region of many miRNAs and, typically, acts as a negative regulator of miRNA gene expression (18). Myc also has indirect effects on miRNA activity through its activation of secondary factors that, in turn, downregulate the antiproliferative, tumor-suppressive, and proapoptotic activities of let-7, miR15a/16-1, miRNA-26a, and miR-34 family members (19). Other miRNAs have been implicated in oncogenic transcription factor pathways, including those mediated by Ras (20) , ZEB1/ZEB2 (21), and p53 and cyclin-dependent kinases (22). Some miRNA regulation also occurs at the post-transcriptional stage (23); for example, the serine/threonine protein kinase IRE1a, which also possesses endoribonuclease activity, cleaves specific pre-miRNAs, thereby reducing the translation of the proapoptotic factor caspase 2 (24) .
In addition to the mechanisms described, studies have demonstrated that miRNA processing can be regulated by other miRNAs. as an example, the miR-103/107 family is known to target expression of Dicer, reducing the levels of a broad spectrum of miRNAs in breast cancer (25) .