BRCA1 Induces Major Energetic Metabolism Reprogramming in Breast Cancer Cells

Abstract

The hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis”, as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. BRCA1 is a major tumor suppressor in breast cancer and it was implicated in numerous pathways resulting in anticarcinogenic functions. The objective of our study was to address specific contributions of BRCA1 to the metabolic features of cancer cells, including the so-called “Warburg effect”. To get a comprehensive approach of the role of BRCA1 in tumor cell metabolism, we performed a global transcriptional and metabolite profiling in a BRCA1-mutated breast cancer cell line transfected or not by wild-type BRCA1. This study revealed that BRCA1 induced numerous modifications of metabolism, including strong inhibition of glycolysis while TCA cycle and oxidative phosphorylation tended to be activated. Regulation of AKT by BRCA1 in both our cell model and BRCA1-mutated breast tumors was suggested to participate in the effect of BRCA1 on glycolysis. We could also show that BRCA1 induced a decrease of ketone bodies and free fatty acids, maybe consumed to supply Acetyl-CoA for TCA cycle. Finally increased activity of antioxidation pathways was observed in BRCA1-transfected cells, that could be a consequence of ROS production by activated oxidative phosphorylation. Our study suggests a new function for BRCA1 in cell metabolic regulation, globally resulting in reversion of the Warburg effect. This could represent a new mechanism by which BRCA1 may exert tumor suppressor function.

Aggressive triple negative breast cancers have unique molecular signature on the basis of mitochondrial genetic and functional defects

“…Moreover, a high percentage of individuals harboring defects (mutations or deletions) in the tumor suppressor gene BRCA1 have receptor triple negative tumors and are at an increased lifetime risk for developing high aggressive breast tumors [62,63]. Interestingly, it has been suggested that BRCA1, a nuclear DNA damage response protein, similar to ATM, is involved in mtDNA maintenance, mtDNA integrity and mtDNA damage repair and regulates cellular metabolism [64]. Our analysis of the TCGA dataset suggests that tumors containing low mtDNA content harbor a higher frequency of pathogenic BRCA1 mutations (Suppl.…”

Racial disparity in metabolic regulation of cancer

“…BRCA1 contributes to various metabolic modifications in cancer cells including inhibition of glycolysis and activation of TCA cycle and oxidative phosphorylation (94). BRCA1 is also known to inhibit energy-consuming anabolic processes such as lipid biosynthesis in cancer cells by interacting with the phosphorylated form of acetyl coenzyme A carboxylase alpha (ACCA), the rate-limiting enzyme that catalyzes de novo fatty acid biogenesis (95).…”

The BRCA1 tumor suppressor: potential long-range interactions of the BRCA1 promoter and the risk of breast cancer

“…It is worth noting, the evidence suggesting that DBS repair pathways are developmentally regulated with HR being crucial in embryonal cells and NHEJ during cell cycles of differentiated cells. DBS repair by HR in primary somatic Recent metabolomics and transcriptomic data further suggests that BRCA1 can cause reversion of aerobic glycolysis (known as a Warburg effect) in breast cancer cells [81].…”