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Estrogen-regulated AGR3 activates the estrogen receptor signaling pathway to promote tamoxifen resistance in breast cancer

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Abstract

Purpose

Anterior gradient 3 (AGR3) is associated with breast cancer progression, but its relationship with estrogen and tamoxifen resistance in breast cancer is still unclear. This study was designed to investigate the correlation of ARG3 and estrogen as well as the roles of ARG3 in tamoxifen resistance in breast cancer.

Methods

Online database including GEPIA, UALCAN, and TCGA and rVista predictive tool were applied to analyze the expression patterns of AGR3 and its relationship with estrogen receptor 1. AGR3 knockdown and overexpression cell models were constructed. Luciferase reporter assay and ChIP were performed to investigate intermolecular interactions. Western blotting and qPCR were applied to assess targets at mRNA and protein levels, respectively. Cell counting and MTT assay were applied to determine the cell proliferation.

Results

An elevation of AGR3 was observed in patients with breast cancer, especially in the patients with estrogen receptor (ER)-positive breast cancer. The TCGA dataset and in vitro data supported that AGR3 was positively correlated to ER. Further results demonstrated that ER protein bound to AGR3 promoter sites. AGR3 expression exhibited a positive correlation to cell viability. Besides, AGR3 promoted tamoxifen resistance in breast cancer.

Conclusion

AGR3 is associated with estrogen and promotes tamoxifen resistance in breast cancer.

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Data availability

Supporting data could be obtained upon reasonable request to the authors.

Abbreviations

AGR3:

Anterior gradient 3

ESR1:

Estrogen receptor 1

ER:

Estrogen receptor

PR:

Progesterone receptor

HER:

Epidermal growth factor receptor

FBS:

Fetal bovine serum

RPMI:

Roswell park memorial institute

qPCR:

Quantitative polymerase chain reaction

ChIP:

Chromatin immunoprecipitation

SD:

Standard deviation

HER:

Hormone receptor

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Funding

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Author notes

  1. Rui Jiang and Yongjie Sun have contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Huaiyin District, Jinan, 250000, China

    Rui Jiang

  2. Department of Breast and Thyroid Diseases, Shandong Second Provincial General Hospital, Shandong Provincial ENT Hospital, No. 4 Duanxing West Road, Huaiyin District, Jinan, 250000, China

    Yongjie Sun

  3. Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, Huaiyin District, Jinan, 250000, China

    Xiao Chen & Peng Shi

Authors
  1. Rui Jiang
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  2. Yongjie Sun
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  3. Xiao Chen
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  4. Peng Shi
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Corresponding author

Correspondence to Peng Shi.

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All the authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethic Committee of Shandong Provincial Hospital affiliated to Shandong First Medical University.

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Jiang, R., Sun, Y., Chen, X. et al. Estrogen-regulated AGR3 activates the estrogen receptor signaling pathway to promote tamoxifen resistance in breast cancer. Breast Cancer Res Treat 190, 203–211 (2021). https://doi.org/10.1007/s10549-021-06385-3

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  • DOI: https://doi.org/10.1007/s10549-021-06385-3

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