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CREB1-BCL2 drives mitochondrial resilience in RAS GAP-dependent breast cancer chemoresistance
Ki-Fong Man1, Omeed Darweesh1,2, Jinghui Hong1,3
1University of Bristol, University Walk, Bristol, UK.
Oncogene
|January 31, 2025
Summary
RASAL2 protein upregulation in triple-negative breast cancer (TNBC) confers chemoresistance by downregulating apoptosis. This RASAL2-BCL2 axis offers a new therapeutic target for resistant TNBC tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
- RASAL2, a RAS GTPase-activating protein, is linked to platinum resistance in TNBC, but its mechanism remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which RASAL2 contributes to chemoresistance in TNBC.
- To identify the molecular pathways regulated by RASAL2 in response to chemotherapy.
Main Methods:
- Analysis of RASAL2 expression in TNBC patient samples post-neoadjuvant chemotherapy.
- In vitro (2D/3D cultures) and in vivo (patient-derived xenograft) models to assess RASAL2 function.
- Investigated apoptotic signaling pathways, YAP activation, and CREB1 transcription factor activity.
- Utilized mitochondrial assays to evaluate apoptosis resistance.
Main Results:
- RASAL2 is specifically enriched in tumor cells after chemotherapy and confers cross-resistance to DNA-damaging agents.
- RASAL2 downregulates apoptosis by upregulating BCL2 expression via YAP activation.
- CREB1 acts as a common transcription factor for both RASAL2 and BCL2.
- Mitochondrial localization of RASAL2 and BCL2 renders mitochondria resistant to apoptosis induction.
Conclusions:
- RASAL2 promotes chemoresistance in a subset of TNBC by inhibiting mitochondrial apoptosis through the RASAL2-YAP-BCL2-CREB1 pathway.
- This study reveals a novel link between RAS GTPase-activating protein function and apoptosis regulation.
- Targeting this pathway presents a potential strategy for overcoming chemotherapy resistance in TNBC.
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