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Brachyury promotes tamoxifen resistance in breast cancer by targeting SIRT1
Kaichun Li1, Mingzhen Ying1, Dan Feng1
1Department of Oncology, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, PR China.
Abstract:
Tamoxifen is effective for treating estrogen receptor-alpha (ERα)-positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. In the present study, we determine the underlying roles of Brachyury in tamoxifen resistance. Loss- and gain-of-function assay are utilized to confirm the oncogenic roles of Brachyury in breast cancer. Compared with the normal MCF10A cells, Brachyury is commonly overexpressed in breast cancer cell lines. Knockdown of Brachyury inhibits tamoxifen resistance, whereas overexpression of Brachyury enhances tamoxifen resistance as demonstrated increased cell viability and reduced cell apoptosis. Mechanistically, we demonstrate for the first time that Brachyury mediates tamoxifen resistance by regulating Sirtuin-1 (SIRT1). Collectively, our data, as a proof of principle, indicate that Brachyury is a candidate marker for predicting the clinical efficacy of tamoxifen and targeting SIRT1 could overcome resistance to tamoxifen in breast cancer cells.
Insights
Brachyury drives tamoxifen resistance in estrogen receptor-alpha-positive breast cancer by regulating Sirtuin-1. Targeting Brachyury or Sirtuin-1 may improve tamoxifen treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tamoxifen is a key treatment for estrogen receptor-alpha (ERα)-positive breast cancer.
- Mechanisms of tamoxifen resistance are not fully understood, limiting treatment effectiveness.
- Identifying novel mediators of resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of Brachyury in tamoxifen resistance in breast cancer.
- To elucidate the molecular mechanisms by which Brachyury influences tamoxifen response.
- To assess Brachyury as a potential predictive marker for tamoxifen efficacy.
Main Methods:
- Utilized loss- and gain-of-function assays to evaluate Brachyury's role in breast cancer.
- Compared Brachyury expression levels in normal breast cells versus breast cancer cell lines.
- Assessed the impact of Brachyury modulation on cell viability and apoptosis in response to tamoxifen.
Main Results:
- Brachyury is overexpressed in breast cancer cell lines compared to normal cells.
- Knockdown of Brachyury reduced tamoxifen resistance, while overexpression enhanced it.
- Brachyury was found to mediate tamoxifen resistance by regulating Sirtuin-1 (SIRT1).
Conclusions:
- Brachyury plays a significant oncogenic role in promoting tamoxifen resistance.
- Brachyury may serve as a predictive biomarker for tamoxifen treatment efficacy.
- Targeting the Brachyury-SIRT1 pathway offers a potential strategy to overcome tamoxifen resistance in breast cancer.
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