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Published on: May 20, 2015
Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer
Che-Pei Kung1, Kyle A Cottrell1, Sua Ryu1
1Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
Abstract:
Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other types of breast cancer that can be effectively treated by targeted therapies, no such targeted therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to prevent sensing of endogenous double-stranded RNAs. ADAR1 is highly expressed in breast cancer including TNBC. Here, we demonstrate that expression of ADAR1, specifically its p150 isoform, is required for the survival of TNBC cell lines. In TNBC cells, knockdown of ADAR1 attenuates proliferation and tumorigenesis. Moreover, ADAR1 knockdown leads to robust translational repression. ADAR1-dependent TNBC cell lines also exhibit elevated IFN stimulated gene expression. IFNAR1 reduction significantly rescued the proliferative defects of ADAR1 loss. These findings establish ADAR1 as a novel therapeutic target for TNBC tumors.
Insights
Triple-negative breast cancer (TNBC) is deadly due to lack of targeted therapies. ADAR1 enzyme is crucial for TNBC cell survival and proliferation, making it a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- RNA Biology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, contributing to its high mortality.
- The ADAR1 enzyme, involved in RNA editing, is upregulated in various cancers, including TNBC.
Purpose of the Study:
- To investigate the role of ADAR1, specifically its p150 isoform, in TNBC cell survival and proliferation.
- To explore ADAR1 as a potential therapeutic target for TNBC.
Main Methods:
- Knockdown of ADAR1 in TNBC cell lines.
- Assessment of proliferation, tumorigenesis, and translational repression.
- Analysis of interferon-stimulated gene expression and IFNAR1 signaling.
Main Results:
- ADAR1 expression, particularly the p150 isoform, is essential for TNBC cell line survival.
- ADAR1 knockdown significantly reduced TNBC cell proliferation and tumorigenesis.
- Loss of ADAR1 function induced translational repression and elevated interferon-stimulated gene expression, which was partially rescued by reducing IFNAR1.
Conclusions:
- ADAR1 plays a critical role in maintaining the viability and proliferation of TNBC cells.
- Targeting ADAR1 presents a promising novel therapeutic strategy for treating triple-negative breast cancer.
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