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

Cited 4 time in Web of Science Cited 3 time in Scopus
Authors
Park, Sin-Aye; Sung, Nam Ji; Choi, Bae-Jung; Kim, Wonki; Kim, Seung Hyeon; Surh, Young-Joon
Issue Date
2020-09
Citation
British Journal of Cancer, Vol.123 No.6, pp.988-999
Abstract
© 2020, The Author(s), under exclusive licence to Cancer Research UK.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.
ISSN
0007-0920
URI
https://hdl.handle.net/10371/172564
DOI
https://doi.org/10.1038/s41416-020-0945-0
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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