Fig. 6

Metabolic dysregulation distinguishes BRCA molecular subtypes and defines therapeutic sensitivity. a Breakdown of 62 significantly dysregulated metabolic pathways in the BRCA pooled data. There is a roughly equal dysregulation of amino acid, carbohydrate, and lipid pathways. b The top pathways dysregulated in BRCA come from a wide variety of major categories, like nucleotides and lipids. However, the two most dysregulated pathways in BRCA are a vitamin-associated pathway, retinol metabolism, and an amino acid pathway, tyrosine metabolism. c Unsupervised clustering of BRCA patients, who were classified based upon the PAM50, on all metabolic genes, reveals a tight cluster of the basal-like subtype (black), which are highly metabolically dysregulated as explained by the magnitude of dysregulation, as displayed in the heatmap. While luminal A (yellow), luminal B (blue), and HER2-expressing (red), did not cluster as tightly, there are still recognizable groups of these patients. d The Top 5 pathways that overlapped between all four subtypes of patients are shown here. While these pathways are highly dysregulated in all four subtypes, they vary to different extents and are almost always highest in the basal-like cells. e After metabolic pathway scoring, pathways unique to the basal-like, and (f) luminal A patients were plotted. The top 5 unique pathways for each of the subtypes are shown. g Targeting the homocysteine biosynthetic pathway with sulfasalazine reveals increased sensitivity in basal-like cells, as compared to luminal A cells, as emphasized by the IC₅₀ values (n = 3). h Targeting the citric acid cycle with metformin reveals increased sensitivity in basal-like cells, as compared to luminal A cells, as emphasized by the IC₅₀ values (n = 3). *Error bars = s.d.