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Identification of hub genes in AR-induced tamoxifen resistance in breast cancer based on weighted gene co-expression network analysis

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Abstract

Background

Approximately 30% of patients with oestrogen receptor (ER)-positive breast cancer (BC) exhibit intrinsic or recurrent resistance to tamoxifen (TAM) adjuvant endocrine therapy. The androgen receptor (AR) is expressed in about 90% of ER-positive patients. Our previous studies found that BC patients with an AR:ER expression ratio ≥ 2.0 are more susceptible to TAM resistance. However, the specific mechanism by which a high AR:ER ratio promotes TAM resistance remains unknown.

Methods

RNA sequencing was performed on 10 cases of BC tissues with AR:ER ratios ≥ 2.0 and 3 cases with AR:ER ratios < 2.0. We then compared our data with the screened TAM-resistant and TAM-sensitive cases from the TCGA BC database. Bioinformatics methods were used to screen differentially expressed genes (DEGs) and to perform gene enrichment analysis. Weighted correlation network analysis (WGCNA) was used to screen hub genes in the AR-induced TAM resistance process.

Results

PAM50 analysis showed that the molecular phenotype of BC patients with

AR:ER ratios ≥ 2.0 was similar to that of triple-negative breast cancer (TNBC), whereas the BC samples with AR:ER ratios < 2.0 were classified as the luminal subtype. Among the AR:ER ratio ≥ 2.0 and AR:ER < 2.0 BC tumours, 1855 DEGs were identified. Gene enrichment analysis showed that DEGs were enriched mainly in proliferation-related molecular pathways, such as the cell cycle, necroptosis, metabolic pathways and DNA replication. WGCNA analysis showed that SEC14L2, RIIAD1, STC2 and MAGEA6 served as hub genes in AR-induced TAM resistance and were associated with BC survival prognosis in the TCGA cohort.

Conclusions

A high AR:ER expression ratio is a biomarker for patients who might develop TAM resistance, and AR expression seems to be a possible mechanism of resistance to endocrine therapy.

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Acknowledgements

We thank the BC patients and their families. They generously donated valuable tissue samples.

Funding

This study was funded by National Natural Science Foundation of China (Grant Number 82002813), Tianjin Health Technology Project (Grant Number TJWJ2021QN010) and Tianjin Key Medical Discipline (Pathology) Construction Project (TJYXZDXK-012A).

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Authors and Affiliations

  1. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China

    Cao Lu, Li Lingmei, Huang Qiujuan, Guo Qianru, Qi Lisha & Cao Wenfeng

  2. Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China

    Yang Yang & Niu Yun

  3. Tianjin University of Science and Technology, Tianjin, 300222, China

    Zhang peisen

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  1. Cao Lu
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  2. Yang Yang
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  3. Li Lingmei
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Contributions

CL and ZPS designed the study; CL, LLM, HQJ and GQR performed the experiments; NY and CWF performed the statistical analysis; CL and ZPS wrote and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zhang peisen.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the ethics committee at the Cancer Hospital of Tianjin Medical University (Ek2020074) and informed consent was obtained from all patients.

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Lu, C., Yang, Y., Lingmei, L. et al. Identification of hub genes in AR-induced tamoxifen resistance in breast cancer based on weighted gene co-expression network analysis. Breast Cancer Res Treat 197, 71–82 (2023). https://doi.org/10.1007/s10549-022-06788-w

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