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GLUT1 participates in tamoxifen resistance in breast cancer cells through autophagy regulation

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Abstract

Tamoxifen is an estrogen modulator widely used in the treatment of patients with ESR/ER-positive breast cancer; however, resistance limits its clinical application. Autophagy alterations have recently been suggested as a new mechanism for tamoxifen resistance. Glucose transporter 1 (GLUT1) has been reported to be associated with the development and metastasis of breast cancer, but the relationship among GLUT1, autophagy, and endocrine resistance remains unclear. Our present study found that GLUT1 expression and autophagy flux were upregulated in the tamoxifen-resistant breast cancer cell line MCF-7/TAMR-1 and that knockdown of GLUT1 promoted sensitization to tamoxifen. Moreover, knockdown of GLUT1 significantly decreased the enhancement of autophagy flux in tamoxifen-resistant cell lines. Furthermore, inhibiting autophagy in tamoxifen-resistant cells resulted in sensitization to tamoxifen. We conclude that GLUT1 contributes to tamoxifen resistance in breast cancer and that tamoxifen-resistant cells become resensitized to tamoxifen after GLUT1 silencing. These findings suggest GLUT1 as a new factor clinically associated with resistance to tamoxifen.

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Abbreviations

Baf-A1:

Bafilomycin A 1

CCK-8:

Cell counting Kit-8

DAB:

Diaminobenzidine

DEGs:

Differentially expressed genes

DFS:

Disease-free survival

DMEM:

Dulbecco’s modified Eagle’s medium

ER/ESR:

Estrogen receptor

FBS:

Fetal bovine serum

FOXO:

Forkhead box O

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GEO:

Gene expression omnibus

GLUT1:

Glucose transporter 1

GO:

Gene Ontology

HRP:

Horseradish peroxidase

IC50:

Inhibitory concentration

KEGG:

Kyoto Encyclopedia of Genes and Genomes

PPI:

Protein-protein interaction

PR:

Progesterone receptor

SEM:

Structural equation modeling

SERMs:

Selective ER modulators

SD:

Standard deviation

siRNA:

Small interfering RNA

siGLUT1:

Small interfering GLUT1

TAM:

Tamoxifen

4OH-T:

4-Hydroxy tamoxifen

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Acknowledgments

The authors would like to thank the Oncobiology Key Lab of the Heilongjiang Province Common Institution of Higher Learning.

Funding

The study was supported by the grants from the National Natural Science Foundation of China (81730074).

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150081, People’s Republic of China

    Mengqi Sun, Shu Zhao & Qingyuan Zhang

  2. Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, People’s Republic of China

    Yuchen Duan

  3. Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150081, People’s Republic of China

    Yumeng Ma

  4. College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150081, People’s Republic of China

    Yicheng Wang

  5. Heilongjiang Cancer Research and Prevention Institute, 150 Haping Road, Harbin, Heilongjiang, 150081, People’s Republic of China

    Hongfei Ji

Authors
  1. Mengqi Sun
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  2. Shu Zhao
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  4. Yumeng Ma
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  7. Qingyuan Zhang
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Contributions

Conception and design: QZ, MS. Development of methodology: MX, SZ, and YD. Acquisition of data: MS, SZ, YW, and YM. Analysis and interpretation of data: MS, SZ, and YM. Writing, review, and/or revision of the manuscript: MS, QZ, and YD. Administrative, technical, or material support: QZ, MS, and SZ. Study supervision: HJ. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qingyuan Zhang.

Ethics declarations

All procedures performed involving human participants in our study were in accordance with the ethical standards of the Institutional and/or research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethics statement

All experiments were performed in the Oncobiology Key Lab of the Heilongjiang Province Common Institution of Higher Learning and were not outsourced to companies. No papermill was used.

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Sun, M., Zhao, S., Duan, Y. et al. GLUT1 participates in tamoxifen resistance in breast cancer cells through autophagy regulation. Naunyn-Schmiedeberg's Arch Pharmacol 394, 205–216 (2021). https://doi.org/10.1007/s00210-020-01893-3

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  • DOI: https://doi.org/10.1007/s00210-020-01893-3

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