YB-1 transforms human mammary epithelial cells through chromatin remodeling leading to the development of basal-like breast cancer.

摘要: There is growing evidence that cancer-initiation could result from epigenetic changes. Y-box binding protein-1 (YB-1) a transcription/translation factor promotes the formation of tumors in transgenic mice; however, underlying molecular events are not understood. To explore this human model system, YB-1 was expressed mammary epithelial cells under control tetracycline-inducible promoter. The induction promoted phenotypes associated with malignancy three-dimensional breast acini cultures. This attributed to enhancing expression and activity histone acetyltransferase p300 leading chromatin remodeling. Specifically, relaxation allowed bind BMI1 engaged Polycomb complex resulting H2A ubiquitylation repression CDKN2A locus. These manifested functionally as enhanced self-renewal capacity occurred BMI1-dependent manner. Conversely, inhibition anacardic acid prevented promoter thereby subverted self-renewal. Despite these early changes, full malignant transformation achieved until RSK2 became overexpressed concomitant elevated telomerase reverse transcriptase (hTERT) activity. YB-1/RSK2/hTERT expressing formed mice were molecularly subtyped basal-like cancer. We conclude cooperates allow over-ride p16(INK4a) -mediated cell cycle arrest enabling development aggressive tumors.