Open AccessGremlin-1 augments the oestrogen-related receptor α signalling through EGFR activation: implications for the progression of breast cancer
Author(s) -
Sin-Aye Park,
Nam Ji Sung,
Byung Yong Choi,
Won-Ki Kim,
Seung Hyeon Kim,
YoungJoon Surh
Publication year - 2020
Publication title -
british journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.833
H-Index - 236
eISSN - 1532-1827
pISSN - 0007-0920
DOI - 10.1038/s41416-020-0945-0
Subject(s) - cancer research , breast cancer , biology , gene knockdown , cancer , chromatin immunoprecipitation , bone morphogenetic protein , cell growth , cell culture , gene expression , promoter , gene , biochemistry , genetics
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.