Regulatory BC200 RNA promotes breast carcinogenesis by repressing BRCA1 gene expression

Downregulation of the BRCA1 gene expression has been implicated in hereditary and sporadic breast cancer. Expression of regulatory BC200 RNA, which is normally restricted to neurons, is dysregulated in invasive breast carcinoma cells, giving rise to high cellular RNA levels. However, the molecular mechanisms by which BC200 RNA contributes to breast cancer malignancy remain poorly understood. Here, we show that atypical BC200 RNA expression in breast epithelial cells results in malignant transformation. By repressing the translation of BRCA1 mRNA, BC200 RNA reduces BRCA1 protein expression in breast epithelial cells, leading to increased DNA damage and carcinogenesis. RNAi-mediated downregulation of BC200 RNA restores the normal, non-malignant phenotype. Tumor innervation stimulates BC200 RNA expression, indicating a role of the nervous system in tumor formation. Thus, in a hitherto unreported molecular mechanism, neuronal BC200 RNA promotes breast carcinogenesis by repressing the expression of the tumor suppressor BRCA1. These findings indicate the utility of BC200 RNA in breast cancer therapy.