HDAC inhibitors target IRS4 to enhance anti‑AR therapy in AR‑positive triple‑negative breast cancer

He,Yang; Ma,Yue; Zhu,Ye; Zhang,Jingyi; Zhao,Shaorong; Zhang,Di; Xu,Danni; Li,Yun; Tong,Zhongsheng; Zhao,Weipeng

doi:10.3892/ijo.2024.5613

HDAC inhibitors target IRS4 to enhance anti‑AR therapy in AR‑positive triple‑negative breast cancer

Authors:
- Yang He
- Yue Ma
- Ye Zhu
- Jingyi Zhang
- Shaorong Zhao
- Di Zhang
- Danni Xu
- Yun Li
- Zhongsheng Tong
- Weipeng Zhao
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Affiliations: Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200031, P.R. China, The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China, Department of General Surgery, Diagnosis and Therapy Centre of Thyroid and Breast, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Hospital, Hefei, Anhui 230001, P.R. China, Department of Pathology, Laboratory Medicine Centre, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310003, P.R. China, The Department of Breast Surgery Ward 2, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: January 12, 2024 https://doi.org/10.3892/ijo.2024.5613
Article Number: 25
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple‑negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Androgen receptor (AR) has been identified as a potential therapeutic target for AR‑positive TNBC; however, clinical trials have not yet produced an effective treatment. The present study aimed to identify a novel treatment regimen to improve the prognosis of AR‑positive TNBC. First, a combination of an AR inhibitor (enzalutamide, Enz) and a selective histone deacetylase inhibitor (chidamide, Chid) was used to treat AR‑positive TNBC cell lines, and a synergistic effect of these drugs was observed. The combination treatment inhibited cell proliferation and migration by arresting the cell cycle at the G₂/M phase. Subsequently, next‑generation sequencing was performed to detect changes in gene regulation. The results showed that the PI3K/Akt signalling pathway was significantly inhibited by the combination treatment of Enz and Chid. Gene Set Enrichment Analysis revealed that the combination group was significantly enriched in KRAS signalling. Analysis of the associated genes revealed that insulin receptor substrate 4 (IRS4) may have a critical role in blocking the activation of KRAS signalling. In a mouse xenograft model, combination treatment also inhibited the PI3K/Akt signalling pathway by upregulating the expression of IRS4 and thereby suppressing tumour growth. In conclusion, the results of the present study revealed that combination treatment with Enz and Chid can upregulate IRS4, which results in the blocking of KRAS signalling and suppression of tumour growth. It may be hypothesised that the expression levels of IRS4 could be used as a biomarker for screening patients with AR‑positive TNBC using Enz and Chid combination therapy.

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