oa TNRC9 (TOX3) downregulates BRCA1 expression and promotes breast cancer aggressiveness

Background: Although the linkage between germline 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 mechanism underlying the downregulation BRCA1 expression is not well understood. It might be dependent upon repressor activity that governs histone acetylation and DNA accessibility at the BRCA1 promoter. TNRC9 (TOX3) gene, highly associated with breast cancer susceptibility, encodes a nuclear protein of uncertain function but can modify chromatin structure. We hypothesized that constitutive expression of TNRC9 could be relevant to breast cancer biology through the modulation of BRCA1 activity. Methods: We assessed the associations of TNRC9 gene amplification with breast cancer onset and survival. The search for targets and effects of TNRC9 was performed using multifaceted molecular approaches. Results: The TNRC9 gene is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. TNRC9 gene amplification is associated with reduced disease-free and metastasis-free survival rates. TNRC9 significantly increased breast cancer cell proliferation, migration and survival of exposure to apoptotic stimuli, and tumor progression both in vitro and in mice models. Gene expression profiling, protein analysis and in silico assays of large datasets of breast and ovarian cancer samples suggested that TNRC9 and BRCA1 expression are inversely correlated. TNRC9 binds not only to BRCA1 promoter but also to the CREB complex, a BRCA1-transcriptional regulator. TNRC9 downregulates the expression of BRCA1 by altering the methylation status of its promoter. Conclusions: Our study unveils a molecular basis for a TNRC9 role in breast cancer and highlights a new paradigm in BRCA1 regulation.