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

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.GREM1knockdown inhibited the proliferation of breast cancer cells and xenograft mammary tumour growth, while its overexpression enhanced their viability, growth and invasiveness. Oestrogen-related receptor alpha (ERR alpha), an orphan nuclear hormone receptor, directly interacted with theGREM1promoter and increased the expression of GREM1. GREM1 also enhanced the promoter activity ofESRRAencoding ERR alpha, comprising a positive feedback loop. Notably, GREM1 bound to and activated EGFR, a well-known upstream regulator of ERR alpha. Conclusions Our study suggests that the GREM1-ERR alpha axis can serve as a potential therapeutic target in the management of cancer, especially ER-negative tumour.