Functional repression of estrogen receptor a by arsenic trioxide in human breast cancer cells
Gui-Cai Chen1, Li-Shuang Guan, Wei-Lian Hu
1School of Life Sciences, Zhejian University, Hangzhou, PR China.
Abstract:
When estrogen binds its receptor (ER), it becomes a potent mitogen in a number of target tissues including the mammary gland where it plays an important role in the pathogenesis of mammary carcinoma. Arsenic trioxide (AS2O3), a clinically effective agent against acute promyelocytic leukemia, has been shown to induce apoptosis in a variety of cancer cells in vitro. Here, we investigated the effects of AS2O3 on the growth of two ER-positive breast cancer cell lines, MCF7 and T47D in vitro. We found that higher doses of AS2O3 dramatically reduced the survival of these two breast cancer cell lines while lower doses of AS2O3 significantly inhibited the expression of estrogen receptor alpha (ER-alpha), but did not effect ER-beta expression. The ER-alpha expression is totally restored when AS2O3 is absent for 24 hours. Using a reporter gene controlled by ER, we further demonstrated that AS2O3 strongly-repressed 17beta-estradiol (E2) stimulated-transcriptional activation. Moreover, AS2O3 abolished transcriptional induction of the estrogen responsive gene pS2 mediated by E2. These results indicated that AS2O3 specifically inhibits expression and signaling pathway of the ER-alpha. We suggest that AS2O3 in combination with other methods might provide a novel therapeutic approach for ER-alpha-positive breast cancer.
Insights
Arsenic trioxide (AS2O3) inhibits estrogen receptor alpha (ER-alpha) expression and signaling in ER-positive breast cancer cells. This suggests AS2O3 as a potential therapeutic agent for ER-alpha-positive breast cancer.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Estrogen receptor (ER) signaling promotes mammary gland cell growth and is implicated in breast cancer pathogenesis.
- Estrogen receptor alpha (ER-alpha) is a key mediator of estrogen's mitogenic effects in breast tissue.
- Arsenic trioxide (AS2O3) exhibits anti-cancer properties, including apoptosis induction in various cancer cells.
Purpose of the Study:
- To investigate the effects of arsenic trioxide (AS2O3) on the growth of estrogen receptor-positive (ER-positive) breast cancer cell lines.
- To determine AS2O3's impact on estrogen receptor alpha (ER-alpha) expression and signaling pathways.
- To evaluate AS2O3 as a potential therapeutic agent for ER-alpha-positive breast cancer.
Main Methods:
- Treatment of ER-positive breast cancer cell lines (MCF7 and T47D) with varying doses of AS2O3 in vitro.
- Assessment of cell survival and ER-alpha and ER-beta expression levels.
- Utilized a reporter gene assay to measure ER transcriptional activity.
- Monitored the expression of the estrogen-responsive gene pS2.
Main Results:
- Higher doses of AS2O3 significantly reduced the survival of MCF7 and T47D cells.
- Lower doses of AS2O3 inhibited ER-alpha expression but not ER-beta expression.
- AS2O3 repressed 17beta-estradiol (E2)-stimulated transcriptional activation mediated by ER.
- AS2O3 abolished E2-induced transcriptional upregulation of the pS2 gene.
- ER-alpha expression was restored upon removal of AS2O3 for 24 hours.
Conclusions:
- AS2O3 specifically inhibits the expression and signaling pathway of ER-alpha in ER-positive breast cancer cells.
- AS2O3 demonstrates potential as a novel therapeutic agent, particularly when used in combination with other treatments for ER-alpha-positive breast cancer.
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