TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness
Menée à l'aide d'un modèle murin et de bases de données d'expression de gènes, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de BRCA1, le gène TNRC9 favorise une forme agressive de cancer du sein
Although the linkage between germ-line mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene TNRC9 (TOX3) has been associated with disease susceptibility but its function is undetermined. Here we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. Gene amplification was associated with reduced disease-free and metastasis-free survival rates. Ectopic expression of TNRC9 increased breast cancer cell proliferation, migration and survival after exposure to apoptotic stimuli. These phenotypes were associated with tumor progression in a mouse model of breast cancer. Gene expression profiling, protein analysis and in silico assays of large datasets of breast and ovarian cancer samples suggested that TNRC9 and BRCA1 expression were inversely correlated. Notably, we found that TNRC9 bound to both the BRCA1 promoter and the CREB complex, a regulator of BRCA1 transcription. In support of this connection, expression of TNRC9 downregulated expression of BRCA1 by altering the methylation status of its promoter. Our studies unveil a function for TNRC9 in breast cancer that highlights a new paradigm in BRCA1 regulation.