RESUMO
BACKGROUND: RSPO ligands, activators of the Wnt/ß-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/ß-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/ß-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/ß-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.
Assuntos
Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Expressão Gênica , RNA Mensageiro/análise , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/tratamento farmacológico , Proliferação de Células , Meios de Cultivo Condicionados/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Imidas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaplasia/genética , Metaplasia/patologia , Camundongos Nus , Transplante de Neoplasias , Quinolinas/uso terapêutico , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas G/genética , Proteína de Ligação a TATA-Box/genética , Trombospondinas/genética , Trombospondinas/metabolismo , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Via de Sinalização Wnt , Proteína Wnt3A/metabolismoRESUMO
Hypercalcaemia is common in some lymphoproliferative disorders such as myeloma or T-cell leukaemia-lymphoma, but is rarely described in B cell chronic lymphocytic leukaemia (BCLL). We report the case of a patient with BCLL, hypercalcaemia and osteolytic bone lesions. Parathyroid hormone-related protein (PTHrP) mRNA was identified by Northern blot analysis of liver, spleen and lymph node tumour samples. Serum levels of tumour necrosis factor alpha (TNF alpha) were increased.
