Deconstructing MYC-Induced Transformation of Human Breast Epithelial Cells

摘要

The c-Myc oncogene is amplified and/or overexpressed in a large number of human malignancies including a significant proportion of breast cancers. It encodes a potent transcription factor that binds to E-box present in promoter regions of many cancerrelevant genes. Despite its prominent role in transformation and cancer, we know very little about its role in breast cancer progression. To understand its role in breast cancer and human mammary (or breast) epithelial cell (HMEC) transformation, we overexpressed c-Myc in HMECs. In this report, we show that overexpression of c-Myc can transform HMECs. We also report that c-Myc overexpression leads to upregulation of polycomb group proteins BMI1 and EZH2. Upregulation of PcG proteins by c-Myc was accompanied by increased histone posttranslational modification activities of PcG proteins. In particular, c-Myc increased the levels of H3K27Me3 (mediated by EZH2). We also report that Myc overexpression led to downregulation of Wnt inhibitors DKK1 and SFRP4, and upregulation of Wnt family members such as WNT2, WNT3, WNT4, WNT5B, WNT7A and WNT16. Since PcG proteins also inhibit expression of Wnt inhibitors, our data suggest that the downregulation of Wnt inhibitors and upregulation of Wnt family members may be mediated by PcG proteins BMI1 and EZH2 that are induced by c-Myc. In summary, Myc, PcGs, Wnt inhibitors and Wnts act in a linear pathway to transform breast epithelial cells.