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
Unit of pharmacogenomics, Department of Genetics, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
Department of Biopathology, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
Br J Cancer. 2017 Jun 6;116(12):1595-1603. doi: 10.1038/bjc.2017.131. Epub 2017 May 4.
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).
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.
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). 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.
RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.
RSPO配体是Wnt/β-连环蛋白信号通路的激活剂，在不同癌症中均有过表达。本研究旨在探究RSPO在乳腺癌（BC）中的作用。
通过qRT-PCR检测乳腺肿瘤及细胞系中RSPO的表达以及各种癌症信号通路的标志物。通过荧光素酶检测、蛋白质免疫印迹法和qRT-PCR确定RSPO对Wnt/β-连环蛋白信号通路活性的影响。使用RSPO2小干扰RNA确定RSPO2抑制对增殖的影响。研究Wnt/β-连环蛋白信号通路抑制剂IWR-1对化生性三阴性乳腺癌患者来源的异种移植瘤（PDX）模型生长的影响。
我们在乳腺癌中检测到RSPO2和RSPO4的过表达水平，尤其是在三阴性乳腺癌（TNBC）、化生性乳腺癌和三阴性细胞系中。多种机制可解释这种过表达：存在涉及RSPO的融合转录本，以及RSPO基因的扩增或低甲基化。RSPO2过表达肿瘤患者的无转移生存期较差（P = 3.6×10）。RSPO2和RSPO4刺激Wnt/β-连环蛋白信号通路活性。在TN细胞系中抑制RSPO表达可抑制细胞生长，IWR-1可显著抑制RSPO2过表达的PDX的生长。
因此，RSPO过表达可能是TNBC的一种新的预后生物标志物和治疗靶点。
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