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ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell
Sandra Udu-Ituma1,2,3, José Adélaïde1, Thi Khanh Le1,3
1Equipe Labellisée Ligue Nationale Contre le Cancer, Predictive Oncology Laboratory, Marseille Research Cancer Center, INSERM U1068, CNRS U7258, Institut Paoli-Calmettes, Aix Marseille University, 13009 Marseille, France.
Abstract:
The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes.
Insights
Researchers developed an antisense oligonucleotide (ASO) to inhibit ZNF703, a gene linked to endocrine resistance in luminal B breast cancer (BC). This ZNF703 inhibition reduced cancer cell growth and increased sensitivity to chemotherapy, offering a new therapeutic strategy for BC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Luminal B breast cancer (BC) is aggressive and often develops resistance to endocrine therapy.
- Estrogen receptor (ER) targeted therapies like tamoxifen are standard treatments, but resistance is a significant clinical challenge.
- Overexpression of the ZNF703 gene has been implicated in BC resistance to endocrine drugs.
Purpose of the Study:
- To investigate ZNF703 as a therapeutic target in luminal B breast cancer.
- To develop and evaluate an antisense oligonucleotide (ASO) for ZNF703 inhibition.
- To assess the efficacy of ZNF703 inhibition alone and in combination with chemotherapy.
Main Methods:
- Development of a ZNF703-specific antisense oligonucleotide (ASO9).
- Assessment of ZNF703 mRNA and protein downregulation.
- Evaluation of cell proliferation and apoptosis assays in BC cells.
- Combination treatment studies with ASO9 and cisplatin.
Main Results:
- The developed ZNF703-ASO9 effectively downregulated ZNF703 protein expression.
- ZNF703 inhibition significantly decreased breast cancer cell proliferation and induced apoptosis.
- Combination therapy with ZNF703-ASO9 and cisplatin demonstrated enhanced anti-cancer effects.
- The study validates ASO technology for targeting previously non-druggable genes like ZNF703.
Conclusions:
- ZNF703 is a promising therapeutic target for overcoming endocrine resistance in luminal B breast cancer.
- Antisense oligonucleotide technology offers a viable strategy for targeting ZNF703 and potentially other challenging cancer-related genes.
- Targeting ZNF703 may improve treatment outcomes for patients with endocrine-resistant breast cancer.
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