Deregulation of the cell cycle by breast tumor kinase (Brk)

作者：Chan Edward; Nimnual Anjaruwee S^*

来源：International Journal of Cancer, 2010, 127(11): 2723-2731.

DOI：10.1002/ijc.25263

• breast tumor kinase
• Brk
• p27
• Cell cycle
• forkhead

Brk is a cytoplasmic nonreceptor tyrosine kinase that is overexpressed in breast tumors but undetectable in normal or benign mammary tissues. Brk promotes proliferation of human mammary epithelial cells and tumor growth in a mouse model, but the role of Brk in cell cycle regulation is not known. In this study, we describe the mechanism of Brk-induced deregulation of the cell cycle. We provide evidence that Brk antagonizes the transcriptional activity of the transcription factor FoxO family of proteins by inhibiting its nuclear localization. As a result, the cell cycle inhibitor p27, a FoxO target gene, is down-regulated. This event is accompanied by G1/S cell cycle progression of quiescent cells. As p27 is a key regulator of the G1/S cell cycle checkpoint, these data suggest that perturbation of p27 expression induced by Brk causes S phase entrance. Deregulation of the cell cycle is a key event in neoplasia, and thus, the mechanism presented here likely contributes to breast cancer development.

• 出版日期2010-12-1