BRCA1 loss-of-function triggers metabolic vulnerability to glutamine deprivation

Abstract

Germline and somatic mutations of BRCA1 are associated with cancer initiation and progression. Although the role of BRCA1 is clearly defined in DNA-repair pathways, alternative functions of BRCA1 still remain obscure. Here, we examined the dependency of isogenic BRCA1 mutant cells to the main metabolic substrates and showed that BRCA1 loss-of-function renders cells more sensitive to glutamine deprivation. Consistently, glutamine deprivation led to more pronounced cell cycle arrest and apoptosis in BRCA1 mutant cells, which also displayed increased glutamine consumption. Incorporation of carbon and nitrogen stable-isotope labelled glutamine indicated an alternative processing of glutamine through the GABA shunt which allows more efficient nitrogen processing. Interestingly, we observed higher glutamate decarboxylase 1 (GAD1) protein levels in BRCA1 mutant cells and an increased sensitivity to GAD1 silencing. This metabolic rewiring also led to increased production of aspartate while other non-essential amino acids were reduced. In line with this, BRCA1 mutant cells displayed lower intracellular nucleotide levels, combined with increased intake and reduced secretion of nucleotide derivatives. Interestingly, the enhanced sensitivity of these cells to glutamine deprivation could be rescued by purine supplementation. Together, these data highlight the role of BRCA1 mutations in driving increased liability to glutamine deprivation and suggest that targeting the GABA shunt may be a novel therapeutic strategy to treat breast cancer patients harbouring BRCA1 mutations.