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Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

Abstract：

BACKGROUND: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). METHODS: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. RESULTS: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. CONCLUSIONS:RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.

journal_name

Br J Cancer

journal_title

British journal of cancer

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

doi

10.1038/bjc.2017.131

subject

Has Abstract

pub_date

2017-06-06 00:00:00

pages

1595-1603

issue

12

eissn

0007-0920

issn

1532-1827

pii

bjc2017131

journal_volume

116

pub_type

杂志文章

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