Estrogen receptor b causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Sreenivasan Paruthiyil Aleksandra Cvoro Mary Tagliaferri Isaac Cohen Emma Shtivelman Dale C. Leitman
- چاپ و سال / کشور: 2010
Description
The role of estrogen receptor beta (ERb) in breast cancer is unclear. ERb is considered to have a protective role in breast cancer development based on findings demonstrating that ERb expression inhibits ERamediated proliferation of breast cancer cells. We previously demonstrated that ERb causes a ligand independent G2 cell cycle arrest in MCF-7 cells. To study the mechanisms of the ERb-mediated G2 cell cycle arrest, we investigated its effects on the regulatory pathways responsible for the G2/M phase transition. We found that ERb inhibits CDK1 activity, which is the critical determinant of the G2/M progression. CDK1 activity is modulated by both stimulatory and inhibitory factors. Cyclin B1 is the major activator of CDK1. ERb inhibited the cell cycle-dependent stimulation of cyclin B1 mRNA and protein. GADD45A and BTG2 are two major inhibitors of CDK1, which have been implicated in breast tumor formation. Based on these findings, we explored if the expression pattern of GADD45A and BTG2 is affected by ERb. We found that ERb stimulates GADD45A and BTG2 mRNA levels. The induction of these two genes is caused by ERb binding directly to these genes and recruiting c-jun and NCOA2. Our findings demonstrated that unliganded ERb causes a G2 cell cycle arrest by inactivating CDK1 through the repression of cyclin B1 and stimulation of GADD45A and BTG2 expression. These results provide evidence that drugs that stimulate the production of unliganded ERb may be effective new therapies to prevent breast cancer.
Breast Cancer Res Treat DOI 10.1007/s10549-010-1273-5 Received: 15 March 2010 / Accepted: 17 November 2010
