Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2

The role of estrogen receptor beta (ER beta) in breast cancer is unclear. ER beta is considered to have a protective role in breast cancer development based on findings demonstrating that ER beta expression inhibits ER alpha-mediated proliferation of breast cancer cells. We previously demonstrated that ER beta causes a ligand independent G2 cell cycle arrest in MCF-7 cells. To study the mechanisms of the ER beta-mediated G2 cell cycle arrest, we investigated its effects on the regulatory pathways responsible for the G2/M phase transition. We found that ER beta 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. ER beta 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 ER beta. We found that ER beta stimulates GADD45A and BTG2 mRNA levels. The induction of these two genes is caused by ER beta binding directly to these genes and recruiting c-jun and NCOA2. Our findings demonstrated that unliganded ER beta 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 ER beta may be effective new therapies to prevent breast cancer.