Abstract
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 breast cancer gene trinucleotide-repeat-containing 9 (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 cAMP-responsive element-binding protein (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.
Highlights
Breast malignancies are a leading cause of female cancerrelated deaths, with an estimated worldwide mortality of more than 458,000 deaths in 2008 [1]
We have shown the clinical implications of trinucleotide-repeat-containing 9 (TNRC9) in breast cancer and uncovered a molecular basis for a TNRC9 role in tumor progression and invasion
Our current findings, showing a significant association between TNRC9 gene amplification and reduction in diseasefree and metastasis-free survival rates, suggest that TNRC9 could be involved in the onset of aggressive forms of breast cancer, found more frequently in Arab populations
Summary
Breast malignancies are a leading cause of female cancerrelated deaths, with an estimated worldwide mortality of more than 458,000 deaths in 2008 [1]. The association of one of these genes, trinucleotide repeat-containing 9 (TNRC9/TOX3), has been further validated by similar GWAS studies in populations of diverse ethnicity, the mechanism by which it confers breast cancer risk is currently unclear [8,9,10,11] This prompted us to investigate what role TNRC9 plays in breast cancer. The potential role of TNRC9 in chromatin structure and function along with the data suggesting that the transcriptional regulation of BRCA1 might be dependent upon epigenetic mechanisms [7] led us to hypothesize that constitutive expression of TNRC9 could be relevant to breast cancer biology through the modulation of BRCA1 activity. Because we observed a high prevalence of the TNRC9 gene amplification in the germline and tumor DNA in the patients with advanced breast cancer, we extended our work with transcriptional and functional analyses to identify a potential mechanism by which TNRC9 may affect breast cancer risk and progression
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