Preventing BRCA 1/ ZBRK 1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation

Breast cancer susceptibility gene 1 (BRCA1) has been implicated in modulating metabolism via transcriptional regulation. However, direct metabolic targets of BRCA 1 and the underlying regulatory mechanisms are still unknown. Here, we identified several metabolic genes, including the gene which encodes glutamate‐oxaloacetate transaminase 2 ( GOT 2), a key enzyme for aspartate biosynthesis, which are repressed by BRCA 1. We report that BRCA 1 forms a co‐repressor complex with ZBRK 1 that coordinately represses GOT 2 expression via a ZBRK 1 recognition element in the promoter of GOT2 . Impairment of this complex results in upregulation of GOT 2, which in turn increases aspartate and alpha ketoglutarate production, leading to rapid cell proliferation of breast cancer cells. Importantly, we found that GOT 2 can serve as an independent prognostic factor for overall survival and disease‐free survival of patients with breast cancer, especially triple‐negative breast cancer. Interestingly, we also demonstrated that GOT 2 overexpression sensitized breast cancer cells to methotrexate, suggesting a promising precision therapeutic strategy for breast cancer treatment. In summary, our findings reveal that BRCA 1 modulates aspartate biosynthesis through transcriptional repression of GOT 2, and provides a biological basis for treatment choices in breast cancer.