MicroRNAs (miRNAs) are ~22 nucleotide small non-coding RNAs that regulate gene expression in many biological processes, mainly at the post-transcriptional level. They are frequently de-regulated in cancer and can act as tumour suppressors or oncogenes. By analysing the small RNA transcriptome of breast cancer cell lines we previously identified a number of small RNAs that are processed from the human vault RNAs by mechanisms partly shared with the miRNA pathway (Persson et al. Nat Cell Biol 2009). We also showed that at least one of these small RNAs associates with Argonaute proteins to guide sequence-specific cleavage and regulate gene expression in a manner similar to miRNAs. CYP3A4, a key enzyme in drug metabolism, was identified as a target gene, perhaps hinting at a tentative explanation for the observed association between vault particles and multidrug resistance.
Through next-generation sequencing of breast tumours and paired samples of normal and tumour-adjacent tissue we have also previously identified hundreds of novel miRNAs (Persson et al. Cancer Res 2010). Interestingly, 10% of the new miRNAs were located in regions with common genomic amplifications in breast cancer. One of these, miR-4728, is located in an intron of the human epidermal growth factor receptor 2 gene (ERBB2) and we have later shown that it regulates expression of oestrogen receptor alpha (ESR1) through a non-canonical seed interaction (Newie et al. PLoS One 2014). We are currently extending our analysis of non-coding RNA expression to a larger set of breast tumours with a focus on biomarker development. In parallel we are also performing functional studies on the novel small RNAs we have identified, especially those produced from the ERBB2 locus.