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Estrogen receptor ?-coupled Bmi1 regulation pathway in breast cancer and its clinical implications.

ABSTRACT: Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ER? and HER2 is undetermined.The expression of Bmi1 and its correlation with ER?, 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 ER? or 17?-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ER?-restored MDA-MB-231 and ER?-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed.Immunostaining revealed strong correlation of Bmi1 and ER? expression status in breast cancer. Expression of Bmi1 was stimulated by 17?-estradiol in ER?-positive MCF-7 cells but not in ER?-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ER?. As expected, stimulation of Bmi1 expression could also be achieved in ER?-restored MDA-MB-231 cells, and at the same time depletion of ER? decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ER? in luciferase assays, and the interaction of the Bmi1 promoter with ER? was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ER?-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.Expression of Bmi1 is influenced by ER?, and the activity of the ER?-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 ER?-coupled Bmi1 in human breast cancer.

SUBMITTER: Wang H

PROVIDER: S-EPMC3939403 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications.

Wang Huali H Liu Haijing H Li Xin X Zhao Jing J Zhang Hong H Mao Jingzhuo J Zou Yongxin Y Zhang Hong H Zhang Shuang S Hou Wei W Hou Lin L McNutt Michael A MA Zhang Bo B

BMC cancer 20140224

<h4>Background</h4>Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERα and HER2 is undetermined.<h4>Methods</h4>The expression of Bmi1 and its correlation with ERα, 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 ERα or 17β-estradiol (E2) was analyzed in cell lines including M ...[more]

PMID: 24559156

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Project description:Breast cancer resistance to the antiestrogens tamoxifen (OHT) and fulvestrant is accompanied by alterations in both estrogen-dependent and estrogen-independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either OHT or fulvestrant. We found that apigenin can function as both an estrogen and an antiestrogen in a dose-dependent manner. At low concentrations (1 mumol/L), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (>10 mumol/L), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either OHT or fulvestrant showed synergistic, growth-inhibitory effects on both antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or an antiestrogen, effects of the drug on estrogen receptor-alpha (ERalpha); transactivation activity, mobility, stability, and ERalpha-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ERalpha and its coactivator amplified in breast cancer-1. However, higher doses (>10 mumol/L) of apigenin inhibited ERalpha mobility (as determined by fluorescence recovery after photobleaching assays), down-regulated ERalpha and amplified in breast cancer-1 expression levels, and inhibited multiple protein kinases, including p38, protein kinase A, mitogen-activated protein kinase, and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and a protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ERalpha-dependent and ERalpha-independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer.

Dataset Information

Estrogen receptor ?-coupled Bmi1 regulation pathway in breast cancer and its clinical implications.

Publications

Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications.

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