The metabolic foibles of triple negative breast cancer

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Science Translational Medicine  25 Nov 2020:
Vol. 12, Issue 571, eabf7102
DOI: 10.1126/scitranslmed.abf7102


Metabolic profiling of triple-negative breast cancers may advance personalized therapies.

Triple-negative breast cancer (TNBC) is the subtype of breast cancer that does not express the estrogen receptor or progesterone receptor and does not overexpress human epidermal growth factor 2. Of all breast cancer subtypes, it carries the worst prognosis and has limited treatment options. Metabolism-targeting therapeutics are an attractive strategy for TNBC; however, TNBC is a heterogeneous disease. Gong and colleagues aimed to understand the metabolic heterogeneity within TNBC to improve specificity of metabolism-targeting therapies.

Through transcriptomic profiling of breast cancers from a cohort of women, the authors identified three metabolic pathway–based subtypes (MPSs) of TNBC. The first subtype, called MPS1, was characterized by up-regulation of lipid synthesis genes, a greater abundance of fatty acids on metabolomic analysis, and a higher prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and phosphatase and tensin homolog (PTEN) mutations than other metabolic subtypes. The second subtype (MPS2) demonstrated up-regulation of glucose and nucleotide metabolism genes, along with decreased glucose abundance and increased concentrations of intermediates of glycolysis and nucleotide metabolism. The third subtype (MPS3) was less well-defined, with mixed metabolic gene expression characteristics. Examining the clinical features of these metabolic subtypes revealed that MPS2 was associated with higher tumor grade and worse relapse-free survival than the other subtypes. They also found that the MPS2 subtype had a gene signature consistent with decreased anti-tumor immune surveillance.

Gong and colleagues next examined whether therapeutically targeting glycolytic metabolism would affect response to anti–programmed cell death protein 1 (PD-1) immunotherapy in vivo, using syngeneic tumor models. They found that inhibiting lactate dehydrogenase improved response to anti–PD-1 therapy and increased the anti-tumor immune response in mice carrying MPS2 tumors but not MPS1 or MPS3 tumors.

These studies reveal the metabolic heterogeneity of TNBC and the importance of understanding this heterogeneity in therapeutic studies. The authors did not examine whether systemic metabolic conditions affected the TNBC metabolic subtype or the response to metabolism-targeting therapies. These questions will be important given the association between metabolic syndrome and TNBC and the links between obesity and response to cancer immunotherapy.

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