ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines

Sandra Udu-Ituma; José Adélaïde; Thi Khanh Le; Kenneth Omabe; Pascal Finetti; Clément Paris; Arnaud Guille; François Bertucci; Daniel Birnbaum; Palma Rocchi; Max Chaffanet

doi:10.3390/pharmaceutics15071930

ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines

Pharmaceutics. 2023 Jul 11;15(7):1930. doi: 10.3390/pharmaceutics15071930.

Authors

Sandra Udu-Ituma^{1

2

3}, José Adélaïde¹, Thi Khanh Le^{1

3}, Kenneth Omabe¹, Pascal Finetti¹, Clément Paris¹, Arnaud Guille¹, François Bertucci¹, Daniel Birnbaum¹, Palma Rocchi^{1

3}, Max Chaffanet¹

Affiliations

¹ Equipe 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.
² Department of Biology, Alex Ekwueme Federal University Ndufu-Alike Ikwo, Abakaliki P.M.B. 1010, Ebonyi State, Nigeria.
³ European Center for Research in Medical Imaging, Aix-Marseille University, 13005 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.

Keywords: ZNF703; antisense oligonucleotides; apoptosis; cisplatin; luminal B breast cancer.

Grants and funding

This work was supported by grants from the Ligue Nationale Contre Le Cancer (labels EL2019 and EL2022 [F.B.]), and R22030AA [P.R.]), ITMO cancer (C21033AS, [P.R.]), Association Ruban Rose (2020 [F.B.]), Fondation Groupe EDF [D.B.], and Canceropole-PACA (2021 [M.C.]). S.U.-I. was supported by a grant from the TETFUND-Tertiary Education Trust Fund/AEFUNAI.