RESUMO
REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFß signaling and that cell-cycle arrest induced by TGFß requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFß signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFß pathway.
Assuntos
Proteínas Nucleares/metabolismo , Proteínas Repressoras/fisiologia , Fator de Crescimento Transformador beta/farmacologia , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA , Humanos , Espectrometria de Massas , Proteínas Nucleares/genética , Proto-Oncogene Mas , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacosRESUMO
The tumour antigen PReferentially expressed Antigen of MElanoma (PRAME) is expressed in a variety of malignancies, including breast cancer. We have analysed PRAME gene expression in relation to clinical outcome for 295 primary breast cancer patients. Kaplan-Meier survival curves show a correlation of PRAME expression levels with increased rates of distant metastases and decreased overall patient survival. This correlation existed both for the entire patient group (n=295) and for the subgroup of patients (n=185) who did not receive adjuvant chemotherapy. Multivariable analysis indicated that PRAME is an independent marker of shortened metastasis-free interval in patients who did not receive adjuvant chemotherapy. PRAME expression was associated with tumour grade and negative oestrogen receptor status. We conclude that PRAME expression is a prognostic marker for clinical outcome of breast cancer, independent of traditional clinicopathological markers.
