Marquez 2013

Epigenetic Dysregulation of microRNAs in Breast Cancer

Rebecca T. Marquez and Liang Xu

Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045

microRNAs are small, 22 nucleotide (nt), non-coding RNAs that repress gene expression by binding to the 3’untranslated region (UTR) of target mRNAs. Dysregulation of microRNA expression levels is a major cause of cancer development. Furthermore, microRNA expression profiles can determine tumor type, patient prognosis, reoccurrence and treatment outcome, with greater accuracy compared to mRNA expression profiles. microRNA expression can be epigenetically dysregulated by aberrant DNA methylation and histone deacetylation in breast cancer cells.   Identifying microRNAs that are epigenetically silenced in breast cancer will provide new insight into breast cancer development as well as define novel signatures for predicting therapeutic response to epigenetic modifying agents. Gene Expression Omnibus datasets of global methylation arrays were used to identify microRNAs that are hypermethylated in breast cancer patient samples. miR-196b is hypermethylated across all breast cancer sub-types compared to normal patient samples.  In addition, miR-196b expression is down-regulated in a subset of breast cancer patient samples, as well as breast cancer cell lines.  miR-196b expression in a breast cancer cell line was re-activated upon treatment with DNA demethylating agent, Decitabine.  Furthermore, reintroducing miR-196b into breast cancer cells using miRNA mimics led to a decrease in colony formation.  This demonstrates a growth inhibitory effect of miR-196b on breast cancer cells. In summary, we have identified a novel breast cancer tumor suppressor miRNA, miR-196b, which is epigenetically dysregulated in breast cancers. Our long-term goal is to establish a miRNA epigenetic signature that will identify patients that will benefit from DNA demethylating agents in combination with other chemotoxic agents.