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UBR5 over-expression contributes to poor prognosis and tamoxifen resistance of ERa+ breast cancer by stabilizing β-catenin

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Abstract

Background

Tamoxifen (TAM) resistance is a critical clinical challenge in the treatment of ERa+ breast cancer. However, the underlying mechanisms involved in TAM-resistance are not fully understood. Here we study the efficacy of UBR5 in predicting TAM-resistance in ERa+ breast cancer.

Methods

Western blot RT-PCR and IHC staining were used to evaluate UBR5 protein and mRNA levels in ERa+ breast cancer cell and tissues. MTT assays and colony formation assays were used to measure cell proliferation. The xeno-graft tumor model was used for in vivo study. We performed protein stability assay and ubiquitin assay to detect β-catenin protein degradation. Immuno-precipitation assay was used to detect the interaction between UBR5 and β-catenin. The ubiquitin-based immuno-precipitation based assay was used to detect the ubiquitination of β-catenin.

Results

High UBR5 expression was correlated with poor prognosis in ER+ breast cancer. Importantly, UBR5 expression was remarkably upregulated in TAM-refractory breast cancer tissues compared with their primary paired TAM-untreated tissues. Additionally, UBR5 overexpression caused tamoxifen-resistance in vitro, whereas UBR5 knockdown increased TAM sensitivity. Mechanistic investigations revealed that UBR5 overexpression, through its ubiquitin ligase catalyzing activity, led to up-regulation of β-catenin expression and activity. Finally, our results confirmed that TAM-resistance promoting effects by UBR5 in ERa+ breast cancer cells was at least partly due to β-catenin stabilization, and inhibition of the UBR5/β-catenin signaling re-sensitizing the resistant breast cancer cells to tamoxifen in vivo.

Conclusions

These findings suggested that UBR5/β-catenin signaling might be a potential therapeutic target for TAM-resistant ERa+ breast cancer.

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Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by National Natural Science Fund of China (Grants 81703786, 81803004 and 81803194).

Author information

Author notes

  1. Yanfang Yang and Jing Zhao are contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Second Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, China

    Yanfang Yang & Gu Lin

  2. Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China

    Yanfang Yang & Gu Lin

  3. Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Ministry of Education, Tianjin Medical University, Tianjin, China

    Yanfang Yang & Gu Lin

  4. Department of Ultrasound Diagnosis, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060, China

    Jing Zhao & Yiran Mao

  5. Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060, China

    Fangxuan Li

  6. Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060, China

    Zhansheng Jiang

Authors
  1. Yanfang Yang
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  2. Jing Zhao
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  3. Yiran Mao
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  4. Gu Lin
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  5. Fangxuan Li
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  6. Zhansheng Jiang
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Contributions

Conception and design: YY, JZ, ZJ. Development of methodology: YY, YM, LG. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.):YY, JZ, YM, FL, ZJ. Writing, review, and/or revision of the manuscript: YY, FL, ZJ. Study supervision: YY, ZJ, FL.

Corresponding authors

Correspondence to Gu Lin, Fangxuan Li or Zhansheng Jiang.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval

This research project was approved by the Ethics Committee of Tianjin Cancer Institute and Hospital.

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Written consents were obtained from each patient to publishing their pathological images as represent Figures.

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10549_2020_5899_MOESM1_ESM.pdf

Supplementary file1 Figure S1: RNA interference sequence of UBR5 and β-catenin. Figure S2: Correlation analysis of UBR5 and β-catenin expression in 1074 BC specimens with RNA sequencing data available from The Cancer Genome Atlas (PDF 298 kb)

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Cite this article

Yang, Y., Zhao, J., Mao, Y. et al. UBR5 over-expression contributes to poor prognosis and tamoxifen resistance of ERa+ breast cancer by stabilizing β-catenin. Breast Cancer Res Treat 184, 699–710 (2020). https://doi.org/10.1007/s10549-020-05899-6

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  • DOI: https://doi.org/10.1007/s10549-020-05899-6

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