Cellular and Molecular Biology

Gremlin-1 augments the oestrogen-related receptor α signalling through EGFR activation: implications for the progression of breast cancer

Subjects

Abstract

Background

Gremlin-1 (GREM1), one of the bone morphogenetic protein antagonists, is involved in organogenesis, tissue differentiation and kidney development. However, the role of GREM1 in cancer progression and its underlying mechanisms remain poorly understood.

Methods

The role of GREM1 in breast cancer progression was assessed by measuring cell viability, colony formation, 3D tumour spheroid formation/invasion and xenograft tumour formation. Chromatin immunoprecipitation, a luciferase reporter assay and flow cytometry were performed to investigate the molecular events in which GREM1 is involved.

Results

GREM1 expression was elevated in breast cancer cells and tissues obtained from breast cancer patients. Its overexpression was associated with poor prognosis in breast cancer patients, especially those with oestrogen receptor (ER)-negative tumours. GREM1 knockdown inhibited the proliferation of breast cancer cells and xenograft mammary tumour growth, while its overexpression enhanced their viability, growth and invasiveness. Oestrogen-related receptor α (ERRα), an orphan nuclear hormone receptor, directly interacted with the GREM1 promoter and increased the expression of GREM1. GREM1 also enhanced the promoter activity of ESRRA encoding ERRα, comprising a positive feedback loop. Notably, GREM1 bound to and activated EGFR, a well-known upstream regulator of ERRα.

Conclusions

Our study suggests that the GREM1–ERRα axis can serve as a potential therapeutic target in the management of cancer, especially ER-negative tumour.

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Fig. 1: GREM1 expression is upregulated in human breast cancer.
Fig. 2: High GREM1 expression is associated with worse outcome in human breast cancer.
Fig. 3: GREM1 regulates the growth of breast cancer cells in vitro and in vivo.
Fig. 4: ERRα increases GREM1 expression.
Fig. 5: GREM1 stimulates EGFR signalling.
Fig. 6: GREM1 increases the transcriptional activity of ERRα and the mRNA levels of ERRα target genes through EGFR activation.

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Contributions

S.-A.P. and Y.-J.S. conceived and designed the experiments; S.-A.P., N.J.S., B.-J.C., W.K. and S.H.K. performed the experiments; S.-A.P., W.K. and S.H.K. analysed the data; S.-A.P. and Y.-J.S. wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Young-Joon Surh.

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All mice were kept under pathogen-free conditions, and all mouse experiments were performed under protocols approved by the Seoul National University Ethics Research Board (SNU-170511-1-1).

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All data and materials generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the Global Core Research Centre (GCRC) Grant (No. 2011-0030001 to Y.-J.S.) from the National Research Foundation (NRF) of Republic of Korea and the Basic Science Research Programme through the NRF of Republic of Korea funded by the Ministry of Education (2017R1A6A3A11032154 to S.-A.P.).

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Park, S., Sung, N.J., Choi, B. et al. Gremlin-1 augments the oestrogen-related receptor α signalling through EGFR activation: implications for the progression of breast cancer. Br J Cancer 123, 988–999 (2020). https://doi.org/10.1038/s41416-020-0945-0

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