Chromatin Remodelling Molecule ARID1A Determines Metastatic Heterogeneity in Triple-Negative Breast Cancer by
Ye Wang1, Xinyu Chen1, Xiaosu Qiao1
1Department of Breast and Urologic Medical Oncology, Fudan University Shanghai Cancer Center, 270, Dong'an Road, Xuhui District, Shanghai 200032, China.
Abstract:
Heterogeneity represents a pivotal factor in the therapeutic failure of triple-negative breast cancer (TNBC). In this study, we retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with TNBC at the Fudan University Cancer Hospital. Our findings show that low ARID1A expression is an independent prognostic indicator for poor overall survival (OS) and recurrence-free survival (RFS) in TNBC patients. Mechanistically, both nuclear and cytoplasmic protein analyses and immunofluorescent localisation assays confirm that ARID1A recruits the Hippo pathway effector YAP into the nucleus in human triple-negative breast cancer cells. Subsequently, we designed a YAP truncator plasmid and confirmed through co-immunoprecipitation that ARID1A can competitively bind to the WW domain of YAP, forming an ARID1A/YAP complex. Moreover, the downregulation of ARID1A promoted migration and invasion in both human triple-negative breast cancer cells and xenograft models through the Hippo/YAP signalling axis. Collectively, these findings demonstrate that ARID1A orchestrates the molecular network of YAP/EMT pathways to affect the heterogeneity in TNBC.
Insights
Low ARID1A expression predicts poor survival in triple-negative breast cancer (TNBC). ARID1A regulates YAP/EMT pathways, impacting TNBC heterogeneity and therapeutic failure.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) heterogeneity contributes to treatment resistance.
- Identifying novel prognostic markers and therapeutic targets is crucial for improving TNBC patient outcomes.
Purpose of the Study:
- To investigate the role of ARID1A expression in TNBC prognosis.
- To elucidate the molecular mechanisms by which ARID1A influences TNBC progression and heterogeneity.
Main Methods:
- Retrospective analysis of clinical and pathological data from 258 TNBC patients.
- Protein localization assays (immunofluorescence, nuclear/cytoplasmic fractionation) and co-immunoprecipitation.
- Functional studies using YAP truncator plasmids in TNBC cell lines and xenograft models.
Main Results:
- Low ARID1A expression is an independent predictor of poor overall survival (OS) and recurrence-free survival (RFS) in TNBC.
- ARID1A interacts with YAP, recruiting it to the nucleus and forming an ARID1A/YAP complex.
- ARID1A downregulation promotes TNBC cell migration and invasion via the Hippo/YAP/EMT signaling axis.
Conclusions:
- ARID1A plays a critical role in regulating TNBC cell behavior and heterogeneity.
- ARID1A acts as a tumor suppressor by modulating the YAP/EMT pathway.
- Targeting ARID1A or its downstream pathways may offer a novel therapeutic strategy for TNBC.
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