title: TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness.
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.
authors: Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar-Qatar Foundation, Qatar.
authors: Jingxuan
authors: J
authors: Shan
authors: Shoba P
authors: SP
authors: Dsouza
authors: Sasha
authors: S
authors: Bakhru
authors: Eman K
authors: EK
authors: Al-Azwani
authors: Maria L
authors: ML
authors: Ascierto
authors: Konduru S
authors: KS
authors: Sastry
authors: Shahinaz
authors: S
authors: Bedri
authors: Dhanya
authors: D
authors: Kizhakayil
authors: Idil I
authors: II
authors: Aigha
authors: Joel
authors: J
authors: Malek
authors: Issam
authors: I
authors: Al-Bozom
authors: Salah
authors: S
authors: Gehani
authors: Stacia
authors: S
authors: Furtado
authors: Edith
authors: E
authors: Mathiowitz
authors: Ena
authors: E
authors: Wang
authors: Francesco M
authors: FM
authors: Marincola
authors: Lotfi
authors: L
authors: Chouchane
mesh_terms: D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D057809:HEK293 Cells; D006609:High Mobility Group Proteins; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D011980:Receptors, Progesterone / Q000378:metabolism*; D015534:Trans-Activators
chemical_list: D051017:Apoptosis Regulatory Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D006609:High Mobility Group Proteins; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators