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RAD51B-EZH2 axis as a potential therapeutic target for TNBC through cell fate conversion
Shiqi Lin1,2,3, Dongyang Tang1,2, Josh Haipeng Lei1,2
1MOE Frontier Science Center for Precision Oncology, University of Macau, Macau SAR, China.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher histologic grade, poorer prognosis, and fewer treatment options due to the lack of reliable and effective molecular targets. Using a functional approach with the Sleeping Beauty (SB) transposon system, we have identified 64 overlapped candidate driver genes for inducing TNBC formation in Brca1-deficient mice and Fgfr2-mutant mice. Further analysis reveals that Rad51b deficiency leads to the development of tumors with a TNBC phenotype by repressing ERα expression through the recruitment of polycomb repressive complex 2 (PRC2) and subsequent trimethylation of histone H3 lysine 27 in Esr1 promoter region. Mechanistically, the loss of RAD51B upregulated cellular ATP levels, followed by the suppression of the AMP-activated protein kinase (AMPK) pathway and dephosphorylation of the Enhancer of zeste homolog 2 (EZH2) at the Thr311 region, which enhances the assembly of PRC2 to repress expression of Esr1. Inhibition of the RAD51B-EZH2 axis allows the re-expression of functional ERα, making TNBC targetable by endocrine therapy. Consistently, the combination of EZH2 inhibitor with tamoxifen effectively reduces TNBC progression, suggesting that the RAD51B-EZH2 axis is a potential therapeutic target for TNBC.
Insights
Triple-negative breast cancer (TNBC) is aggressive, lacking targets. Rad51b deficiency represses ERα, creating TNBC. Targeting the RAD51B-EZH2 axis re-expresses ERα, making TNBC treatable with endocrine therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic targets.
- Identifying novel molecular drivers is crucial for developing effective treatments for TNBC.
Purpose of the Study:
- To identify candidate driver genes involved in TNBC formation.
- To elucidate the molecular mechanisms underlying TNBC development and identify potential therapeutic targets.
Main Methods:
- Utilized the Sleeping Beauty (SB) transposon system for functional screening in mouse models (Brca1-deficient and Fgfr2-mutant).
- Investigated the role of Rad51b deficiency in TNBC development and ERα repression.
- Analyzed the involvement of Polycomb Repressive Complex 2 (PRC2), histone modifications, and the AMPK pathway.
Main Results:
- Identified 64 overlapped candidate driver genes for TNBC induction.
- Demonstrated that Rad51b deficiency represses estrogen receptor alpha (ERα) expression via PRC2 recruitment and H3K27 trimethylation.
- Showed that RAD51B loss upregulates ATP, suppresses AMPK, and dephosphorylates EZH2, enhancing PRC2 activity and repressing Esr1.
Conclusions:
- The RAD51B-EZH2 axis is a key regulator of ERα expression in TNBC.
- Inhibiting this axis can restore ERα expression, rendering TNBC susceptible to endocrine therapy.
- Combination therapy with an EZH2 inhibitor and tamoxifen shows promise in reducing TNBC progression.
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