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- Title
Clinical value of R-spondins in triple-negative and metaplastic breast cancers.
- Authors
Coussy, F; Lallemand, F; Vacher, S; Schnitzler, A; Chemlali, W; Caly, M; Nicolas, A; Richon, S; Meseure, D; El Botty, R; De-Plater, L; Fuhrmann, L; Dubois, T; Roman-Roman, S; Dangles-Marie, V; Marangoni, E; Bièche, I; Bièche, I
- Abstract
<bold>Background: </bold>RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC).<bold>Methods: </bold>Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/β-catenin pathway, was examined on the growth of an RSPO2-positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC.<bold>Results: </bold>We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO, and amplification or hypomethylation of RSPO genes. Patients with RSPO2-overexpressing tumours have a poorer metastasis-free survival (P=3.6 × 10-4). RSPO2 and RSPO4 stimulate Wnt/β-catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2-overexpressing PDX.<bold>Conclusions: </bold>RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.
- Subjects
ANTINEOPLASTIC agents; QUINOLINE; ORGANIC compounds; BREAST cancer chemotherapy; RNA analysis; ANIMAL experimentation; BREAST cancer; BREAST tumors; CELL physiology; CELL receptors; CELLULAR signal transduction; CULTURE media (Biology); EPITHELIAL cells; GENE expression; GLYCOPROTEINS; GROWTH factors; METAPLASIA; MICE; PROTEINS; RNA; DUCTAL carcinoma; THERAPEUTICS
- Publication
British Journal of Cancer, 2017, Vol 116, Issue 12, p1595
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/bjc.2017.131