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DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer

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Abstract

Background

Tamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear.

Methods

The expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays.

Results

Our results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling.

Conclusions

Our research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer.

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Availability of data and materials:

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

The study is supported by the National Natural Foudation of China (No. 81902675, Recipient: Yawei Shi); the Natural Science Foudation of Guangdong Province (No. 2021A1515010333, Recipient: Yawei Shi); the Guangdong Medical Science and Technology Foundation (No.A2018069, Recipient: Yawei Shi).

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Authors and Affiliations

  1. The Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan Two Road, 510080, Guangzhou, Guangdong, China

    **aoli Liang, Zeng Fang, Nan Shao, Duanyang Zhai, Mengmeng Zhang, Liang Yu & Yawei Shi

  2. The Department of Vascular surgery, the Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, 510000, Guangzhou, Guangdong, China

    Yang Zhao

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  1. **aoli Liang
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Contributions

YMS and LY designed the research. DYZ, MMZ, YZ and ZF performed the experiments. NS performed the statistical analysis. XLL and YZ collected the data and wrote the paper. All authors read and approved the final content of the study.

Corresponding authors

Correspondence to Liang Yu or Yawei Shi.

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The authors declare that they have no competing interests.

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The manuscript has not been previously published or submitted in whole or in part elsewhere. Before gathering the patient tissues for research, the approval from the Institutional Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University were obtained.

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Before collecting human specimens, we obtained patient consent and approval from the Institutional Research Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University.

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All authors read the final manuscript and agreed on the publication.

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Liang, X., Zhao, Y., Fang, Z. et al. DLGAP1-AS2 promotes estrogen receptor signalling and confers tamoxifen resistance in breast cancer. Mol Biol Rep 49, 3939–3947 (2022). https://doi.org/10.1007/s11033-022-07244-0

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  • DOI: https://doi.org/10.1007/s11033-022-07244-0

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