Role of miR-143 Regulating DNA Methyltransferases 3A in Breast Cancer.

Abstract

Abstract Background and Aims: MicroRNAs (miRNAs) are 19-25-nucleotides regulatory non-protein-coding RNA molecules that regulate the expressions of a wide variety of genes including some involved in cancer development. In particular, decreased expression of miR-143 has been reported in various human cancers including colorectal cancer and B-cell lymphomas. The aim of this study was to elucidate the role of miR-143 dysregulation in breast cancer.Methods: Expression levels of human mature microRNAs (miRNAs) were compared with paired breast carcinomas and adjacent normal tissues by TaqMan real-time PCR based expression arrays. Decreased expression of miR-143 was further confirmed in breast cancer cell lines and paired breast tumors and normal adjacent tissues by qRT-PCR. Potential targets of miR-143 were defined. The functional effect of miR-143 and its targets was performed in human breast cancer cell lines to confirm target association.Results: Down-regulation of miR-143 was verified in both human breast cancer cell lines and 80% (12/15) of breast tumors (P < 0.001). DNA methyltranferase 3A (DNMT3A), one of a key enzyme involved in DNA methylation, was defined as a potential target of miR-143 by in-silico analysis. Overexpression of miR-143 in breast cancer cell lines down-regulated expression of DNMT3A, decreased tumor cell growth by MTT assay and soft agar colony formation assay. DNMT3A was demonstrated to be a direct target of miR-143 by luciferase reporter assay. Inverse correlation between DNMT3A protein and miR-143 was found in tumor and normal breast tissues.Conclusions: In this study, we show for the first time in breast cancer that miR-143 specifically targeted DNMT3A and the expression of miR-143 was inversely correlated with DNMT3A expression. Our findings demonstrated that down-regulation of miR-143 and up-regulation of DNMT3A are significant changes in breast tumors. These findings indicate a tumor suppressive role of miR-143 in epigenetic aberration of breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3148.