Abstract
BackgroundGremlin-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.MethodsThe 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.ResultsGREM1 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.ConclusionsOur study suggests that the GREM1–ERRα axis can serve as a potential therapeutic target in the management of cancer, especially ER-negative tumour.
Highlights
Gremlin-1 (GREM1), one of the bone morphogenetic protein antagonists, is involved in organogenesis, tissue differentiation and kidney development
GREM1 is overexpressed in human breast cancer, which is associated with worse survival of breast cancer patients As an initial approach to assess a role of GREM1 in breast cancer development, we first examined the level of GREM1 in some transformed or cancerous human breast cell lines as compared to non-cancerous human breast epithelial cells (MCF-10A)
Extracellular GREM1 was detected in the collected conditioned media from control breast cancer cells (MDA-MB453-shCtrl and SKBR3-shCtrl), while it was undetectable in GREM1depleted cells (MDA-MB-453-shGREM1 and SKBR3-shGREM1)
Summary
Gremlin-1 (GREM1), one of the bone morphogenetic protein antagonists, is involved in organogenesis, tissue differentiation and kidney development. Its overexpression was associated with poor prognosis in breast cancer patients, especially those with oestrogen receptor (ER)negative tumours. Gremlin-1 (GREM1) is a member of the cystine knot superfamily and a bone morphogenetic protein (BMP) antagonist.[5,6] GREM1 plays a critical role in embryogenesis, organ development and tissue differentiation through regulation of BMPs.[7,8] In addition, GREM1 has been involved in diverse pathological conditions, such as renal[9,10] or pulmonary fibrosis,[11,12] renal inflammation[13,14] and diabetic kidney disease[15,16] in BMP-dependent or -independent manners. GREM1 is well known to induce fibrosis of organs, which requires the epithelial–mesenchymal transition (EMT) process.[9,17]
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