Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERalpha and HER2 is undetermined.
Methods:
The expression of Bmi1 and its correlation with ERalpha, PR, Ki-67, HER2, p16INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERalpha or 17beta-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERalpha-restored MDA-MB-231 and ERalpha-knockdown MCF-7 cells.
Luciferase reporter and chromatin immunoprecipitation assays were also performed.
Results:
Immunostaining revealed strong correlation of Bmi1 and ERalpha expression status in breast cancer. Expression of Bmi1 was stimulated by 17beta-estradiol in ERalpha-positive MCF-7 cells but not in ERalpha-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERalpha.
As expected, stimulation of Bmi1 expression could also be achieved in ERalpha-restored MDA-MB-231 cells, and at the same time depletion of ERalpha decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERalpha in luciferase assays, and the interaction of the Bmi1 promoter with ERalpha was confirmed by chromatin immunoprecipitation.
Moreover, in breast cancer tissues activation of the ERalpha-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer.
Conclusions:
Expression of Bmi1 is influenced by ERalpha, and the activity of the ERalpha-coupled Bmi1 signature impacts p16INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERalpha-coupled Bmi1 in human breast cancer.
Author: Huali WangHaijing LiuXin LiJing ZhaoHong ZhangJingzhuo MaoYongxin ZouHong ZhangShuang ZhangWei HouLin HouMichael A McNuttBo Zhang
Credits/Source: BMC Cancer 2014, 14:122
Published on: 2014-02-24
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