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Updated: Mar 27, 2026
Monitoring of Nanodrug Accumulation in Murine Breast Cancer Metastases
Published on: August 23, 2024
BMAL1 silencing as a promising chemosensitizing strategy for triple-negative breast cancer
Lu-Yi Wang1,2,3,4, Xue-Han Xu1,2,3,4, Wen-Jing Xuan2,3,4
1School of Materials Science and Engineering, Zhejiang University, Hangzhou, 310058, China.
Abstract:
Circadian genes are closely associated with tumor development and its sensitivity to chemotherapeutic agents. In triple-negative breast cancer (TNBC), the core circadian gene BMAL1 exhibits an aberrant expression pattern, but its mechanism of influencing TNBC chemosensitivity remains unknown. In this study, we demonstrate that BMAL1 acts as an oncogene in TNBC. Using BMAL1 siRNA-loaded lipid nanoparticles (LNPs), we effectively silenced BMAL1 expression both in vitro and in vivo, resulting in enhanced apoptosis and reduced proliferation of TNBC cells. Notably, BMAL1 suppression following chemotherapy-induced DNA damage impairs the RPA-ATR-CHK1 DNA repair axis, leading to S-phase arrest and accumulation of unrepaired DNA damage. This synergistically increases the sensitivity of TNBC cells to etoposide. Our findings reveal BMAL1 as a promising therapeutic target and support the potential of silencing BMAL1 with siRNA as a neoadjuvant strategy in combination with chemotherapeutic agents for the treatment of TNBC.
Insights
BMAL1, a core circadian gene, drives triple-negative breast cancer (TNBC) growth. Silencing BMAL1 with siRNA enhances chemotherapy sensitivity by disrupting DNA repair, offering a new therapeutic strategy for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Chronobiology
Background:
- Circadian genes influence tumor development and chemotherapy response.
- Aberrant expression of the core circadian gene BMAL1 is observed in triple-negative breast cancer (TNBC).
- The precise mechanism by which BMAL1 affects TNBC chemosensitivity is not fully understood.
Purpose of the Study:
- To investigate the role of BMAL1 in TNBC.
- To explore the potential of BMAL1 suppression as a therapeutic strategy for TNBC.
Main Methods:
- Utilized BMAL1 siRNA-loaded lipid nanoparticles (LNPs) for gene silencing.
- Evaluated the effects of BMAL1 suppression on TNBC cell proliferation and apoptosis in vitro and in vivo.
- Assessed the impact of BMAL1 suppression on DNA damage repair pathways and chemosensitivity to etoposide.
Main Results:
- BMAL1 was identified as an oncogene in TNBC.
- BMAL1 silencing via siRNA-LNPs reduced TNBC cell proliferation and increased apoptosis.
- BMAL1 suppression impaired the RPA-ATR-CHK1 DNA repair axis following chemotherapy-induced DNA damage.
- This impairment led to S-phase arrest, accumulation of DNA damage, and synergistic enhancement of etoposide sensitivity in TNBC cells.
Conclusions:
- BMAL1 acts as an oncogene in TNBC, promoting proliferation and conferring chemoresistance.
- Targeting BMAL1 with siRNA represents a promising therapeutic strategy.
- Combining BMAL1 silencing with chemotherapy could serve as a neoadjuvant treatment for TNBC.
